Organic Syntheses, Coll. Vol. 4, p.780 (1963); Vol. 35, p.91 (1955).

Organic Syntheses, Coll. Vol. 5, p.157 (1973); Vol. 44, p.15 (1964).t-BUTYL AZIDOFORMATE[Formic acid, azido-, tert-butyl ester]Submitted by Louis A. Carpino, Barbara A. Carpino, Paul J. Crowley, Chester A. Giza, and PaulH. Terry1.Checked by Virgil Boekelheide and S. J. Cross.1. ProcedureIn a 1-l. round-bottomed flask fitted with a mechanical stirrer are placed 82 g. (0.62 mole) of t-butyl carbazate,2 72 g. of glacial acetic acid, and 100 ml. of water. The solution is cooled in an ice bath, and 47.0 g. (0.68 mole) of solid sodium nitrite is added over a period of 40–50 minutes, the temperature being kept at 10–15° (Note 1). The mixture is allowed to stand in the ice bath for 30 minutes, 100 ml. of water is added, and the floating oil is extracted into four 40-ml. portions of ether. The combined ether extracts are washed twice with 50-ml. portions of water and with 40-ml. portions of 1M sodium bicarbonate solution until no longer acidic (about three washings are required). The solution is dried over magnesium sulfate, and the ether is removed by distillation from a water bath maintained at 40–45°; water aspirator pressure of 140–150 mm. is used. The pressure is then lowered to 70 mm., and the water bath temperature is raised to 90–95°. The azide is distilled (Caution! (Note 2)) using a Claisen flask and is collected at 73–74° (70 mm.), n24D 1.4227, after a few drops of fore-run. The yield is 57–72.8 g. (64–82%) (Note 3) and (Note 4).2. Notes1. The sodium nitrite may be added as a concentrated aqueous solution.2. It is recommended that the distillation be carried out behind a safety shield. The submitters have distilled this compound several hundred times without incident under the conditions given on a scale up to 300–400 g. per run. On the other hand, Prof. P. G. Katsoyannis (University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania) has reported that an explosion took place in the receiving flask while the compound was being distilled under conditions previously used without incident. The reason for the explosion could not be traced. According to Prof. R. Schwyzer (Ciba, Ltd., Basel, Switzerland) tests at a Swiss Federal Institute showed that the compound could not be exploded by mere heating: it simply decomposes. For explosion, one must apply a primary explosive such as lead azide or silver azide. An attempt by the submitters to distil the azide at atmospheric pressure resulted in vigorous carbonization, but no explosion occurred. In view of the potential hazard some investigators prefer not to distil the azide; they use the crude material after removal of solvent. High yields of carbo-t-butoxy derivatives may be obtained in this way.3. When freshly distilled, the azide is water-white. When the azide is allowed to stand for several weeks, it slowly develops a light yellow color; however, this does not appear to affect its reactivity as an acylating agent.34. The azide should be handled with adequate ventilation. Careless inhalation of the substance was accompanied by development of a painful throbbing headache or a sensation of giddiness or both. These effects disappeared within several hours upon exposure to fresh air.3. Discussiont-Butyl azidoformate has been prepared by a variety of procedures,3,4,5,6,7,8,9,10,11,12 of which the present procedure and that described elsewhere in this series12appear most satisfactory.Because of the instability of t-butyl chloroformate a number of carbonic acid derivatives have been prepared and studied as reagents for the introduction of the carbo-t-butoxy group. A listing of these reagents and references to their preparation may be found in reference 13. In spite of some disadvantages the most widely used reagent is still t-butyl azidoformate, although t-butyl 2,4,5-trichlorophenyl-carbonate appears to be another potentially useful reagent. t-Butyl azidoformate is a convenient reagent for the acylation of amines, hydrazines, and similar compounds.3The acylation product of hydroxylamine, t-butyl N-hydroxycarbamate,5 is a valuable intermediate in the synthesis of O-substituted hydroxylamines such as O-acyl- and O-sulfonylhydroxylamines, many of which are valuable aminating agents and have not be obtained in any other way.14,15 This preparation is referenced from:z Org. Syn. Coll. Vol. 5, 160z Org. Syn. Coll. Vol. 6, 199z Org. Syn. Coll. Vol. 6, 203z Org. Syn. Coll. Vol. 6, 207z Org. Syn. Coll. Vol. 6, 418z Org. Syn. Coll. Vol. 7, 70References and Notes1.Department of Chemistry, University of Massachusetts, Amherst, Massachusetts.2.L. A. Carpino, D. Collins, and S. Göwecke, this volume, p. 166.3.L. A. Carpino, J. Am. Chem. Soc., 79, 4427 (1957).4.L. A. Carpino, J. Am. Chem. Soc., 79, 98 (1957).5.L. A. Carpino, C. A. Giza, and B. A. Carpino, J. Am. Chem. Soc., 81, 955 (1959).6.K. P. Polzhofer, Chimia (Aarau), 23, 298 (1969).7.H. Yajima and H. Kawatani, Chem. Pharm. Bull. (Tokyo), 16, 182 (1968).8.M. Itoh and D. Morino, Experientia, 24, 101 (1968).9.Y. A. Kiryushkin and A. I. Miroshnikov, Experientia, 21, 418 (1965).10.K. Inouye, M. Kanayama, and H. Otsuka, Nippon Kagaku Zasshi, 85, 599 (1964).11. D. S. Tarbell, Accounts Chem. Res., 2, 296 (1969).12.M. A. Insalaco and D. S. Tarbell, Org. Syntheses, 50, 9 (1970).13.L. A. Carpino, K. N. Parameswaran, R. K. Kirkley, J. W. Spiewak, and E. Schmitz, J. Org.Chem., 35, 3291 (1970).14.L. A. Carpino, J. Am. Chem. Soc., 82, 3133 (1960).15.L. A. Carpino, J. Am. Chem. Soc., 85, 2144 (1963).AppendixChemical Abstracts Nomenclature (Collective Index Number);(Registry Number)acetic acid (64-19-7)ether (60-29-7)sodium bicarbonate (144-55-8)sodium nitrite(7632-00-0)hydroxylamine (7803-49-8)magnesium sulfate (7487-88-9)silver azidet-BUTYL AZIDOFORMATE,Formic acid, azido-, tert-butyl ester (1070-19-5)t-butyl carbazate (870-46-2)t-butyl chloroformatet-butyl 2,4,5-trichlorophenyl-carbonate (16965-08-5)t-butyl N-hydroxycarbamate (36016-38-3)lead azideCopyright © 1921-2005, Organic Syntheses, Inc. All Rights Reserved。

经典化学合成反应标准操作醛酮的经典合成目录1．前言 (4)2．由醇合成醛酮 (4)2.1铬（VI）试剂 (4)2.1.1 Jones氧化（Cr2O3/H2SO4/acetone） (4)2.1.2 Collins氧化（Cr2O3.2Py） (5)2.1.3 PCC（Pyrindium Chlorochromate）氧化 (8)2.1.4 PDC（Pyrindium Dichromate）氧化 (9)2.2 用活性MnO2氧化 (10)2.2.1 用活性MnO2氧化示例一: (10)2.3用DMSO氧化 (11)2.3.1 DMSO-(COCl)2氧化（Swern Oxidation） (11)2.3.2 DMSO-SO3-Pyridine (12)2.4 用氧铵盐氧化 (13)2.4.1 用氧铵盐氧化示例： (13)2.5 用高价碘试剂氧化 (14)2.5 .1 Dess-Martin氧化反应示例： (14)2.5.2 IBX氧化反应示例： (15)2.6 亚硝酸钠和醋酐氧化 (15)2.6.1 亚硝酸钠和醋酐氧化示例 (15)2.6 TPAP-NMO 氧化 (16)2.6.1 TPAP-NMO 氧化示例 (16)2.7 1,2-二醇的氧化 (16)2.7.1 1,2-二醇的氧化示例一： (17)2.7.1 其他1,2-二醇的氧化相关文献： (18)3．由卤化物合成醛酮 (18)3.1 由伯卤甲基和仲卤甲基的氧化合成醛酮 (18)3.1.1 用DMSO氧化（Kornblum反应） (18)3.1.2用硝基化合物氧化（Hass反应） (20)3.1.3用乌洛托品氧化（Sommelet反应） (21)3.1.4用对亚硝基二甲苯胺氧化吡啶翁盐氧化（Kröhnke反应） (22)3.1.5用胺氧化物氧化 (22)3.2 由二卤甲基或二卤亚甲基合成醛酮 (23)3.2.1 由二卤甲基合成醛反应示例： (23)3.3 由有机金属化合物的酰化合成醛酮 (24)3.3.1 由有机金属化合物的酰化合成醛酮示例 (25)3.4 由Pd催化反应合成醛 (25)4．由活泼甲基或活泼亚甲基烷烃合成醛酮 (25)4.1 用SeO2氧化合成醛酮 (26)4.1.1 用SeO2氧化合成醛酮示例 (26)4.2用空气氧化合成酮 (26)4.2.1用空气氧化合成酮反应示例： (27)4.3 用铬酸氧化合成酮 (27)4.3.1 用铬酸氧化合成酮示例 (27)4.4用高锰酸盐氧化合成酮 (29)4.5 用醌氧化合成酮 (29)5．由羧酸及其衍生物合成醛酮 (30)5.1由羧酸合成醛 (30)5.1.1用金属氢化物还原 (30)5.1.2由脱CO2合成醛 (31)5.1.3由羧酸合成酮 (31)5.2由酰氯及酸酐合成醛酮 (33)5.2.1用Rosenmund法合成 (33)5.2.2用金属氢化物还原 (34)5.3由酯及内酯合成醛 (35)5.3.1 酯通过DIBAL还原为醛示例： (36)5.4由酰胺合成醛酮 (36)5.4.1 由酰胺合成醛酮 (37)5.4.2 McFadyen-Stevens Reaction (38)5.5由酯或酰氯经Weinreb酰胺合成醛酮 (39)5.5.1 由Weinreb酰胺还原合成醛反应示例一 (40)5.5.2由Weinreb酰胺还原合成酮反应示例: (41)5.6由氰合成醛酮 (41)5.6.1DIBAL 还原腈到醛示例（最重要的方法） (42)5.6.2Li(EtO)3AlH 还原腈到醛示例（较重要的方法） (43)5.6.3Ranney Ni 加氢还原氰到合成醛示例 (43)5.6.4有机金属试剂对腈加成合成酮示例 (44)6. 由烯烃、芳环合成醛酮 (46)6.1 由烯烃臭氧氧化合成醛 (46)6.2 烯烃用OsO4/NaIO4氧化合成醛 (47)6.3 烯烃经由有机硼化合物中间体的烯烃甲酰化合成醛 (47)6.5 由烯烃的甲酰化合成醛 (48)6.5.1 Vilsmeyer反应 (48)6.5.2 Duff’s 甲酰化 (51)6.5.3 Reimer-Tiemann 甲酰化 (52)6.5.4 Gattermann甲酰化 (53)6.5.5 多聚甲醛/甲醇镁苯酚甲酰化 (53)6.5.6氯化锡/多聚甲醛苯酚甲酰化 (54)6.5.7重氮化后甲酰化 (54)6.6烯烃经加成-氧化反应合成酮 (56)6.6.1 烯烃经加成-氧化反应合成酮示例 (56)7. 由炔烃合成醛酮 (57)7.1 由加成-氧化反应合成醛酮 (57)7.2 由氧化反应合成酮 (57)7.3 由加成-水解反应合成酮 (58)7.4 由加成-还原反应合成酮 (59)7.5 由加成-烷基化，酰化等反应合成酮 (59)8. 由醚及环氧化合物合成醛酮 (59)8.1 Claisen重排 (59)8.2酸催化下环氧化物重排 (61)8.2.1 酸催化下环氧化物重排合成醛酮示例一 (61)8.3氧化法 (61)8.4 水解法缩醛或酮合成醛酮 (61)9. 由胺合成醛 (62)9.1胺的氧化 (62)9.1.1 胺的氧化合成醛反应示例： (63)9.2 由胺经由西佛碱的方法 (64)9.2.1 由胺经由西佛碱合成醛示例 (64)9.3 自苯胺衍生物合成 (64)10. 由硝基化合物合成醛酮 (64)11. 由Friedel-Crafts反应合成芳基酮 (65)11.1 由Friedel-Crafts反应合成芳基酮示例 (68)12. Dieckmann 缩合脱酸 (69)13. 由合成子合成醛酮 (71)14. 由砜合成醛酮 (71)15. Michael 反应和类似反应(Addition, Condensation) (71)1．前言醛和酮是一类重要的有机化合物，其合成在有机合成中占有非常重要的地位。

Organic Syntheses, Coll. Vol. 2, p.351 (1943); Vol. 19, p.55 (1939).IODOBENZENE[Benzene, iodo-]Submitted by H. J. Lucas and E. R. Kennedy.Checked by John R. Johnson and P. L. Barrick.1. ProcedureIn a 3- or 5-gallon stoneware crock are placed 950 cc. (1130 g., 11.7 moles) of concentrated hydrochloric acid (sp. gr. 1.19), 950 cc. of water, 200 g. (196 cc., 2.15 moles) of aniline, and 2 kg. of ice (Note 1). The mixture is agitated by a mechanical stirrer, and, as soon as the temperature drops below 5°, a chilled solution of 156 g. (2.26 moles) of sodium nitrite in a measured volume (700–1000 cc.) of water is introduced fairly rapidly from a separatory funnel, the stem of which projects below the surface of the reaction mixture. The addition should not be fast enough to cause the temperature to rise to 10° or to cause evolution of oxides of nitrogen. The last 5 per cent of the nitrite solution is added more slowly, and the reaction mixture is tested with starch-iodide paper at intervals until an excess of nitrous acid is indicated.Stirring is continued for ten minutes, and if necessary the solution is filtered rapidly through a loose cotton plug in a large funnel. An aqueous solution of 358 g. (2.16 moles) of potassium iodide is added and the reaction mixture allowed to stand overnight. The mixture is transferred to a large flask (or two smaller flasks) and heated on a steam bath, using an air-cooled reflux condenser, until no more gas is evolved, then allowed to cool and stand undisturbed until the heavy organic layer has settled thoroughly.A large part of the upper aqueous layer is siphoned off, and discarded (Note 2). The residual aqueous and organic layers are made alkaline by the cautious addition of strong sodium hydroxide solution (100–125 g. of solid technical sodium hydroxide is usually required) and steam-distilled at once. The last one-third of the steam distillate is collected separately and combined with the aqueous layer separated from the earlier portions of the distillate. This mixture is acidified with 5–10 cc. of concentrated sulfuric acid and steam-distilled again. The iodobenzene from this operation is combined with the main portion and dried with 10–15 g. of calcium chloride(Note 3) and (Note 4). Distillation under reduced pressure gives 327–335 g. (74–76 per cent of the theoretical amount) of iodobenzene, b.p. 77–78°/20 mm. or 63–64°/8 mm. (Note 5).2. Notes1. If more ice is used a portion remains unmelted after the diazotization is completed.2. If a good separation has been made not more than 1–2 g. of iodobenzene is lost with the upper layer.3. An appreciable amount of iodobenzene is retained by the solid calcium chloride. By treating the spent drying agent with water 8–12 g. of iodobenzene can be recovered.4. The crude iodobenzene weighs 350–355 g. (80 per cent of the theoretical amount) and is pure enough for many purposes without redistillation.5. If the distillation is carried too far, the distillate will be colored.3. DiscussionThe preparation of iodobenzene by iodination of benzene, with iodine and nitric acid, and a survey of preparative methods have been given in an earlier volume.1 The present procedure, based upon the method of Gattermann,2 gives a purer product.This preparation is referenced from:z Org. Syn. Coll. Vol. 5, 660z Org. Syn. Coll. Vol. 5, 665References and Notes. Syn. Coll. Vol. I, 1941, 323.2.Gattermann-Wieland, "Laboratory Methods of Organic Chemistry," p. 283. Translated from thetwenty-fourth German edition by W. McCartney, The Macmillan Company, New York, 1937.AppendixChemical Abstracts Nomenclature (Collective Index Number);(Registry Number)oxides of nitrogencalcium chloride (10043-52-4)sulfuric acid (7664-93-9)hydrochloric acid (7647-01-0)Benzene (71-43-2)aniline (62-53-3)sodium hydroxide (1310-73-2)nitric acid (7697-37-2)potassium iodide (7681-11-0)sodium nitrite (7632-00-0)nitrous acid (7782-77-6)iodine (7553-56-2)Iodobenzene,Benzene, iodo-(591-50-4)Copyright © 1921-2005, Organic Syntheses, Inc. All Rights Reserved。

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(19)中华人民共和国国家知识产权局(12)发明专利(10)授权公告号 (45)授权公告日 (21)申请号 201910004035.5(22)申请日 2019.01.03(65)同一申请的已公布的文献号申请公布号 CN 109608361 A (43)申请公布日 2019.04.12(73)专利权人 山东国邦药业有限公司地址 261108 山东省潍坊市滨海经济开发区先进制造产业园香江西一街02131号院内专利权人 国邦医药集团股份有限公司(72)发明人 王友杰　李琦斌　王伟宏　(74)专利代理机构 潍坊正信致远知识产权代理有限公司 37255代理人 刘德林(51)Int.Cl.C07C 253/18(2006.01)C07C 255/03(2006.01)(56)对比文件CN 106278945 A ,2017.01.04CN 108424375 A ,2018.08.21US 5770757 A ,1998.06.23Yuecheng Zhang等.Amination of allyl alcohol to …… hydrogenation reactions.《Applied Catalysis A: General》.2013,第467卷154-162.Yuecheng Zhang等.Amination of allyl alcohol to propionitrile over a Zn30Cr4.5/γ-Al2O3 bimetallic catalyst via coupled dehydrogenation –hydrogenation reactions.《Applied Catalysis A: General》.2013,第467卷154-162.审查员 姜雪(54)发明名称一种二氯乙腈的合成方法(57)摘要本发明公开了一种二氯乙腈的合成方法，包括以下步骤：向四氯乙烯加入二氯甲烷，然后向二氯甲烷‑四氯乙烯体系中缓慢通入氨气升压，并使用水浴进行升温，并保温保压进行反应，反应结束后降温，并排清剩余的氨气，通过蒸馏收集馏分得到二氯乙腈。

Organic Syntheses, Coll. Vol. 10, p.107; Vol. 78, p.82EFFICIENT SYNTHESIS OF HALOMETHYL-2,2'-BIPYRIDINES:4,4'-BIS(CHLOROMETHYL)-2,2'-BIPYRIDINE[ 2,2'-Bipyridine, 4,4'-bis(chloromethyl)- ]Submitted by Adam P. Smith, Jaydeep J. S. Lamba, and Cassandra L. Fraser 1 .Checked by Motoki Yamane and Koichi Narasaka. 1. ProcedureA. 4,4'-Bis[(trimethylsilyl)methyl]-2,2'-bipyridine . A 500-mL, two-necked, round-bottomed flask (Note 1), equipped with a nitrogen inlet, magnetic stirrer, and rubber septum is charged with tetrahydrofuran (THF) (90 mL) (Note 2) and diisopropylamine (9.8 mL, 69.7 mmol) (Note 3). The reaction mixture is cooled to −78°C and a solution of butyllithium (n-BuLi) (1.7 M in hexanes, 36.0 mL, 61.4 mmol) (Note 4) is added. The solution is stirred at −78°C for 10 min, warmed to 0°C and stirred for 10 min, then cooled back to −78°C. A solution of 4,4'-dimethyl-2,2'-bipyridine (5.14 g, 27.9 mmol) (Note 5) in THF (130 mL) (Note 2), prepared in a 250-mL, two-necked, round-bottomed flask under a nitrogen atmosphere, is added via cannula to the cold lithium diisopropylamide (LDA) solution. The resulting maroon-black reaction mixture is stirred at −78°C for 1 hr, then chlorotrimethylsilane (TMSCl) (8.85 mL, 69.7 mmol) (Note 6) is rapidly added via syringe. After the solution becomes pale blue-green (≈10 sec after the TMSCl addition), the reaction is quenched by rapid addition of absolute ethanol (10 mL). (Note: the reaction should be quenched regardless of color change after a maximum of 15 seconds to avoid over silylation). The cold reaction mixture is poured into a separatory funnel (1 L) containing aqueous saturated sodium bicarbonate (NaHCO 3, ≈200 mL) and allowed to warm to ≈25°C. The product is extracted with dichloromethane (CH 2Cl 2, 3 × 300 mL); the combined organic fractions are shaken with brine (≈200 mL) and dried over sodium sulfate (Na 2SO 4). Filtration and concentration on a rotary evaporator affords 8.85 g (97%) of 4,4'-bis[(trimethylsilyl)methyl]-2,2'-bipyridine as a slightly off-white crystalline solid (Note 7).B. 4,4'-Bis(chloromethyl)-2,2'-bipyridine . Into a 500-mL, two-necked, round-bottomed flask (Note 1) equipped with a magnetic stirring bar are placed 5.22 g (15.9 mmol) of 4,4'-bis[(trimethylsilyl)methyl]-2,2'-bipyridine , 15.1 g (63.6 mmol) of hexachloroethane (Cl 3CCCl 3, Note 8) and 9.65 g (63.6 mmol) of cesium fluoride (CsF, Note 9) at 25°C under a nitrogen atmosphere. Acetonitrile (260 mL) (Note 10) is added and the heterogeneous reaction mixture is stirred at 60°C for ≈3.5 hr (or until TLC indicates that all TMS starting material is consumed). After the mixture is cooled to 25°C, it is poured into a separatory funnel containing ethyl acetate (EtOAc) and water (H 2O, ≈100 mL each). The product is extracted with EtOAc (3 × 100 mL); the combined organic fractions are shaken with brine (≈200 mL) and dried over Na 2SO 4. Filtration and concentration on a rotary evaporator, followed by flashchromatography using deactivated silica gel (60% EtOAc: 40% hexanes)(Note 11), gives 3.67 g (91%) of the chloride as a white solid (Note 12).2. Notes1. Before use, all glassware, needles, and syringes were dried overnight in a 120°C oven.2. THF was dried and purified by passage through alumina solvent purification columns 2 or by distillation over sodium /benzophenone .3. Diisopropylamine was purchased from Aldrich Chemical Company, Inc. , and distilled over calcium hydride (CaH 2) prior to use.4. A 1.7 M solution of n-BuLi in hexanes was obtained from Aldrich Chemical Company, Inc. The n-BuLi is titrated prior to its use in each reaction using the following procedure.3 To a 50-mL, round-bottomed flask (Note 1), equipped with nitrogen inlet and a magnetic stirrer is added N-benzylbenzamide (854 mg, 4.0 mmol) (as received from Aldrich Chemical Company, Inc.) and THF (40 mL) (Note 2). The solution is cooled to −42°C (acetonitrile /dry ice) and n-BuLi is added dropwise to the blue endpoint (color persists for >30 sec). The molarity is calculated using a 1:1 stoichiometric ratio of N-benzylbenzamide to n-BuLi. (Just greater than 1 equivalent of alkyllithium is needed to reach the endpoint).5. 4,4'-Dimethyl-2,2'-bipyridine was obtained from GFS Chemicals, Inc. or Tokyo Chemical Industry Co. and used as received.6. Chlorotrimethylsilane (TMSCl) was purchased from Aldrich Chemical Company, Inc. , and used as obtained.7. The following characterization data was obtained: mp 90-92°C; 1H NMR (CDCl 3, 300 MHz) δ: 0.04 (s, 18 H), 2.21 (s, 4 H), 6.94 (d, 2 H, J = 5.01),8.05 (br s, 2 H), 8.46 (d, 2 H, J = 5.00) ; 13C NMR (CDCl 3, 75 MHz) δ: −2.2, 27.1, 120.4, 123.0, 148.3, 150.8, 155.5 . Anal. Calcd for C 18H 28N 2Si 2: C, 65.79; H, 8.59; N, 8.53. Found: C, 65.78; H, 8.43; N, 8.76. It has been noted that desilylation occurs after standing in deuterochloroform (CDCl 3) overnight. The resulting methyl derivatives have also been observed in certain purified TMS bipyridine samples when stored over time. Therefore, it is best to convert these intermediates to the corresponding halides in a timely fashion. 8. Hexachloroethane (Cl 3CCCl 3), obtained from Aldrich Chemical Company, Inc. , was used as received.9. Cesium fluoride was purchased from Acros Organics, Inc. or Soekawa Chemicals Co. and stored in a dry box prior to use. 10. Acetonitrile was distilled over CaH 2 and stored in a 500-mL Kontes flask prior to use. 11. Silica gel used for flash chromatography (particle size 0.035-0.075 mm) was obtained from VWR Scientific Products . Silica chromatography columns were deactivated by flushing with 10% triethylamine in hexanes and then were washed with hexanes prior to use. 12. Spectral properties are as follows: mp 98-100°C; 1H NMR (CDCl 3, 300 MHz) δ: 4.63 (s, 4 H), 7.38 (dd, 2 H, J = 1.9, 5.0), 8.43 (s, 2 H), 8.70 (d, 2 H, J = 4.6) ; 13C NMR (CDCl 3, 75 MHz) δ: 43.9, 120.1, 122.8, 146.7, 149.4, 155.8 . Anal. Calcd for C 12H 10Cl 2N 2: C, 56.94; H, 3.98; N, 11.07. Found: C, 56.82; H, 4.04; N, 11.01. 13. In some cases, particularly if the solvent or reaction conditions are not thoroughly dry, 4,4'-dimethyl-2,2'-bipyridine is formed as a byproduct during the halogenation reaction. This compound may be separated from 4,4'-bis(chloromethyl)-2,2'-bipyridine by flash chromatography on silica gel (not deactivated with Et3N) using EtOAc as the mobile phase. Alternatively, 4,4'-bis(chloromethyl)-2,2'-bipyridine may be purified by recrystallization in hot/cold absolute EtOH, with no evidence of ether formation (e.g., 4,4'-di-Ethoxymethyl-2,2'-bipyridine) by 1H NMR.Waste Disposal InformationAll toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.3. DiscussionHalomethylbipyridines, are typically synthesized either by radical halogenation 4 or from hydroxymethylbipyridine precursors.5Radical methods often give rise to mixtures of halogenatedspecies that are difficult to separate with flash chromatography. A solution to this problem, involving the selective reduction of polyhalogenated by-products with diisobutylaluminum hydride (DIBAL-H), has resulted in slight improvements in overall yields.6 While the synthesis of halomethyl compounds from hydroxymethyl precursors is more efficient than radical halogenation, such procedures involve many steps, each of which give intermediates in moderate to high yields.5 Direct trapping of bpy (CH 2Li)n with electrophiles has proved unsuccessful for the generation of halide products.5a The quenching of LDA-generated carbanions with TMSCl prior to halogenation as described here constitutes an efficient, high yield synthesis of halomethyl bpys substituted at various positions around the ring system.7,8Currently, 2,2'-bipyridine derivatives figure prominently in supramolecular assembly,9 in bioinorganic contexts,10 in studies of redox electrocatalysis 4a and in polymeric materials.11 Halomethyl bpys and their various metal complexes have also been used as initiators for controlled polymerizations of several different monomers including styrene and 2-alkyl-2-oxazolines.12TABLE I SYNTHESIS OF (TRIMETHYLSILYL)METHYL-2,2'-BIPYRIDINESProductR 1 R 2 R 3 R 4 Yield (%)4-(Trimethylsilyl)-methyl-2,2'-bipyridineTMSCH 2H H H 935-(Trimethylsilyl)-methyl-2,2'-bipyridineH TMSCH 2H H 996-(Trimethylsilyl)-methyl-2,2'-bipyridineH H TMSCH 2H 974,4'-Bis[(trimethylsilyl)-methyl]-2,2'-bipyridineTMSCH 2H H TMSCH 297TABLE II SYNTHESIS OF HALOMETHYL-2,2'-BIPYRIDINES Product R 1 R 2 R 3 R 4 Yield (%)4-Chloromethyl-2,2'-bipyridineClCH 2H H H94 5-Chloromethyl-2,2'-bipyridineH ClCH 2H H98 6-Chloromethyl-2,2'-bipyridineH H ClCH 2H 95 4,4'-Bis(chloromethyl)-2,2'-bipyridineClCH 2H H ClCH 291 4-Bromomethyl-2,2'-bipyridineBrCH 2H H H925-Bromomethyl-2,2'-bipyridineH BrCH 2H H986-Bromomethyl-2,2'-bipyridine H H BrCH 2H 99References and Notes1.Department of Chemistry, University of Virginia, Charlottesville, VA 22904-4319.2.Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics1996, 15, 1518.3.Burchat, A. F.; Chong, J. M.; Nielsen, N. J. Organomet. Chem. 1997, 542, 281.4.(a) Gould, S.; Strouse, G. F.; Meyer, T. J.; Sullivan, B. P. Inorg. Chem. 1991, 30, 2942 andreferences therein; (b) Wang, Z.; Reibenspies, J.; Motekaitis, R. J.; Martell, A. E. J. Chem. Soc., Dalton Trans. 1995, 1511; (c) Rodriguez-Ubis, J.-C.; Alpha, B.; Plancherel, D.; Lehn, J.-M. Helv. Chim. Acta 1984, 67, 2264; (d) Newkome, G. R.; Puckett, W. E.; Kiefer, G. E.; Gupta, V. K.; Xia, Y.; Coreil, M.; Hackney, M. A. J. Org. Chem. 1982, 47, 4116.5.(a) Della Ciana, L.; Hamachi, I.; Meyer, T. J. J. Org. Chem. 1989, 54, 1731; (b) Della Ciana, L.;Dressick, W. J.; Von Zelewsky, A. J. Heterocycl. Chem. 1990, 27, 163; (c) Newkome, G. R.; Kiefer, G. E.; Kohli, D. K.; Xia, Y.-J.; Fronczek, F. R.; Baker, G. R. J. Org. Chem. 1989, 54, 5105; (d) Imperiali, B.; Prins, T. J.; Fisher, S. L. J. Org. Chem. 1993, 58, 1613.6.Uenishi, J.; Tanaka, T.; Nishiwaki, K.; Wakabayashi, S.; Oae, S.; Tsukube, H. J. Org. Chem.1993, 58, 4382.7.Fraser, C. L.; Anastasi, N. R.; Lamba, J. J. S. J. Org. Chem. 1997, 62, 9314.8.Savage, S. A.; Smith, A. P.; Fraser, C. L. J. Org. Chem. 1998, 63, 10048.9.(a) Boulas, P. L.; Gómez-Kaifer, M.; Echegoyen, L. Angew. Chem., Int. Ed. Engl. 1998, 37, 216;(b) Mamula, O.; von Zelewsky, A.; Bernardinelli, G. Angew. Chem., Int. Ed. Engl. 1998, 37, 290. 10.(a) Gray, H. B.; Winkler, J. R. Annu. Rev. Biochem. 1996, 65, 537; (b) Dandliker, P. J.; Holmlin,R. E.; Barton, J. K. Science 1997, 275, 1465.11.For a recent review see: Matyjaszewski, K., Ed. "Controlled Radical Polymerizations"; AmericanChemical Society: Washington, DC, 1998.12.(a) Collins, J. E.; Fraser, C. L. Macromolecules 1998, 31, 6715; (b) McAlvin, J. E.; Fraser, C. L. Macromolecules 1999, 32, 1341; (c) Wu, X.; Fraser, C. L. Macromolecules 2000, 33, 4053.AppendixChemical Abstracts Nomenclature (Collective Index Number);(Registry Number)4,4'-Bis(chloromethyl)-2,2'-bipyridines :2,2'-Bipyridine, 4,4'-bis(chloromethyl)- (13); (138219-98-4)4,4'-Bis[(trimethylsilyl)methyl]-2,2'-bipyridine :2,2'-Bipyridine, 4,4'-bis[(trimethylsilyl)methyl]-(14); (199282-52-5) 4,4'-Bis(bromomethyl)-2,2'-bipyridineBrCH 2H H BrCH 297Diisopropylamine (8);2-Propanamine, N-(1-methylethyl)- (9); (108-18-9)Butyllithium:Lithium, butyl- (8,9); (109-72-8)4,4'-Dimethyl-2,2'-bipyridine:2,2'-Bipyridine, 4,4'-dimethyl- (9); (1134-35-6)Chlorotrimethylsilane:Silane, chlorotrimethyl- (8,9); (75-77-4)Hexachloroethane:Ethane, hexachloro- (8,9); (67-72-1)Cesium fluoride (8,9); (13400-13-0)Acetonitrile: TOXIC (8,9); (75-05-8)N-Benzylbenzamide:Benzamide, N-benzyl- (8);Benzamide, N-(phenylmethyl)- (9); (1485-70-7) Copyright © 1921-2002, Organic Syntheses, Inc. All Rights Reserved。

Organic Syntheses, Coll. Vol. 2, p.464 (1943); Vol. 13, p.84 (1933).NITROSOMETHYLURETHANE[Carbamic acid, methylnitroso-, ethyl ester]Submitted by W. W. Hartman and Ross Phillips.Checked by Louis F. Fieser and J. T. Walker.1. ProcedureTo 206 g. (2 moles) of ethyl N-methylcarbamate(p. 278) and 600 cc. of ordinary ethyl ether in a 5-l. flask is added, along with 200 g. of ice, 650 g. (9 moles) of 96 per cent sodium nitrite(Note 1) dissolved in 1 l. of cold water. The flask is provided with a stopper carrying a thermometer, a tube to lead off evolved nitric oxide, and a separatory funnel with an extension tube reaching to the bottom of the flask. A solution of 1.2 kg. (6.7 moles) of cold 35 per cent nitric acid, prepared by pouring 600 g. (426 cc.) of concentrated acid onto 600 g. of ice, is then cautiously added through the funnel in the course of one and one-half hours. The flask is given an occasional swirl to ensure some mixing, but most of the stirring is done by the evolved gases. Ice is added as required to keep the temperature below 15°. The ether layer first becomes pale red and gradually changes to a blue-green. As soon as the color has changed to green, the ether layer is separated (Note 2), washed twice with cold water, and then with cold potassium carbonate solution until carbon dioxide is no longer evolved. The solution is dried with solid potassium carbonate, and the ether is distilled from a water bath using a 1-l. flask with a 30-cm. column arranged for vacuum distillation. The vacuum is applied as soon as most of the ether has been removed, and the flask is heated gently so that the temperature of the liquid does not exceed 45–50° (Note 3) until the pressure has been reduced below 20 mm. The yield of nitrosomethylurethane boiling at 59–61/10 mm. is 200 g. (76 per cent of the theoretical amount). The density is 1.133 at 20°.2. Notes1. A large excess of sodium nitrite is required to give a satisfactory yield. This may be due to reaction according to the following equations: Nitric oxide (NO) is lost during the reaction. It is not thought advisable to use this by passing in oxygen because of the danger of an explosion, or by passing in air because of the loss of material by evaporation.2. Nitrosomethylurethane irritates the skin.3. According to the literature, nitrosomethylurethane explodes when attempts are made to distil it at normal pressure.3. DiscussionNitrosomethylurethane has been prepared by treating ethyl methylcarbamate with sodium nitrite and sulfuric acid,1 and by passing the gases generated from arsenious oxide and nitric acid into an ethereal solution of ethyl methylcarbamate.2This preparation is referenced from:z Org. Syn. Coll. Vol. 3, 119z Org. Syn. Coll. Vol. 4, 780z Org. Syn. Coll. Vol. 5, 842References and Notes1.Klobbie, Rec. trav. chim. 9, 139 (1890).2.v. Pechmann, Ber. 28, 856 (1895); Schmidt, ibid. 36, 2477 (1903); Brühl, ibid. 36, 3635 (1903).AppendixChemical Abstracts Nomenclature (Collective Index Number);(Registry Number)arsenious oxideNitric oxide (NO)potassium carbonate (584-08-7)sulfuric acid (7664-93-9)ether,ethyl ether (60-29-7)nitric acid (7697-37-2)oxygen (7782-44-7)sodium nitrite (7632-00-0)carbon dioxide (124-38-9)nitric oxideNitrosomethylurethaneEthyl N-methylcarbamate,ethyl methylcarbamate (105-40-8)Carbamic acid, methylnitroso-, ethyl ester (615-53-2)Copyright © 1921-2005, Organic Syntheses, Inc. All Rights Reserved。

eluant (Note 7) to give 9.0 g (59% overall) of (2R,3S)- and (2S,3S)-1,4-dioxa-2,3-dimethyl-2-(1-methylethenyl)-8-carboethoxy-8-azaspiro[4.5]decane, a 6:1 mixture of diastereomers, as a pale yellow oil (Note 8).B. (2S,3S)-3-Acetyl-8-carboethoxy-2,3-dimethyl-1-oxa-8-azaspiro[4.5]decane. Dry nitromethane (100 mL) (Note 9) is added through a rubber septum by syringe to a vacuum-dried, 500-mL, round-bottomed flask that contains the ketal mixture prepared in Step A (9.00 g, 31.8 mmol) and a magnetic stir bar. The solution is cooled to −23°C, tin(IV) chloride (SnCl4) (11 mL, 94 mmol) is added by syringe and the solution is stirred for 30 min at −23°C (Note 10). At this time the brown solution is warmed to 23°C and stirring is continued for an additional 30 min. Saturated aqueous NH4Cl (200 mL) is added and the mixture is concentrated under reduced pressure using a rotary evaporator to remove nitromethane. The resulting aqueous suspension is extracted with ethyl acetate (200 mL) and the organic extract is washed with brine (200 mL), dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure using a rotary evaporator. The residue is subjected to flash chromatography on silica gel (250 g, 20 cm × 10 cm) using ethyl acetate:hexane (1:1) eluant (Note 7) to give 8.1 g (90%) of (2S,3S)-3-acetyl-8-carboethoxy-2,3-dimethyl-1-oxa-8-azaspiro[4.5]decane as a pale yellow oil (Note 11) and (Note 12).2. Notes1. Anhydrous tetrahydrofuran was prepared by distillation under argon from sodium benzophenone ketyl.2. 2-Bromopropene, obtained from Aldrich Chemical Company, Inc., was distilled and then passed through a plugof activity IV basic alumina immediately before use.3. The fine white emulsion formed at this stage was collected with the organic phase and was cleared in the subsequent brine washings.4. This crude material was acceptable for use in the second step, although more p-toluenesulfonic acid will be required if large amounts of tributylamine are present. The diol mixture, free from tributylamine, can be obtained by careful chromatography on silica gel using ethyl acetate-hexane (1:1). The purified sample has the following characteristics: 1H NMR (500 MHz, CDCl3, major isomer) δ: 1.10 (d, 3 H, J = 6.5, CH3), 1.37 (s, 3 H, CH3), 1.80 (s,3 H, CH3), 2.21 (br s, 2 H, 2 × OH), 3.77 (q, 1 H, J = 5.6, CH), 4.89 (d, 1 H, J = 1.1, CH=C), 5.06 (s, 1 H, CH=C); IR (film) cm−1: 3421, 3397, 3390, 3364, 2981, 2937, 1088; MS (Cl) m/z 113.0936 (113.0966 calcd for C7H14O2, MH –H2O).5. The major isomer is assigned the 3R, 4S stereochemistry on the expectation that the addition would occur preferentially with Cram (Felkin-Ahn) selectivity.3 This assignment was confirmed by 1H NMR DNOE experimentson the isobutyraldehyde acetal.6. 1-Carbethoxy-4-piperidone was obtained from Aldrich Chemical Company, Inc., and used as received.7. A series of 200-mL fractions was collected during flash chromatography. The product was eluted in fractions3–8 as indicated by TLC analysis using 4% ethanolic phosphomolybdic acid stain.8. This sample has the following characteristics: 1H NMR (500 MHz, CDCl3, major isomer) δ: 1.17 (d, 3 H, J =5.1, CH3), 1.26 (t, 3 H, J = 7.1, OCH2CH3), 1.45 (s, 3 H, CH3), 1.77 (s, 3 H, CH3C=), 1.60–1.81 (m, 5 H, 2 × CH2and CH), 3.43–3.75 (m, 4 H, 2 × CH2N), 4.13 (q, 2 H, J = 7.1, OCH2CH3), 4.96 (s, 2 H, CH2=C); IR (film) cm−1: 2977, 1702, 1433, 1238, 1122; MS (Cl) m/z 284.1850 (284.1861 calcd for C15H25NO4, MH). Anal. Calcd forC15H25NO4: C, 63.58; H, 8.89; N, 4.94. Found: C, 63.48; H, 8.90; N, 4.89.9. Nitromethane was dried by distillation of a 10:1 mixture of nitromethane and trifluoroacetic anhydride and collection of the center fraction that distilled at 100°C.10. Tin(IV) chloride (SnCl4) was obtained from Aldrich Chemical Company, Inc., and handled under an atmosphere of argon.11. Gas chromatographic analysis using a 25-m 10% SP 2100 silicone column showed that this sample was 94% pure and contained one major unidentified impurity. Bulb-to-bulb distillation (200°C, 0.6 mm) of a 7.4-g sample of the crude product afforded 7.0 g (85%) of the product as a pale yellow oil, which was shown by GLC analysis to be of 100% purity. This sample has the following spectral characteristics: [α]D−79.1° (MeOH, c 1.0); 1H NMR (500 MHz, CDCl3) δ: 1.17 (d, 3 H, J = 6.6, CH3), 1.25 (m, 6 H, OCH2CH3 and CH3), 1.70–1.90 (m, 4 H, 2 × CH2), 2.19 (s, 3 H,CH3CO), 1.57 (d, 1 H, J = 13.5) 2.36 (d, 1 H, J = 13.5), 3.38–3.70 (m, 4 H, 2 × CH2N), 3.89 (q, 1 H, J = 6.6, CH)4.12 (q, 2 H, J = 7.1, OCH2CH3); 13C NMR (125 MHz, CDCl3) δ: 14.5, 15.6, 22.5, 28.3, 36.0, 37.0, 40.7, 41.1, 47.3, 58.4, 61.0, 79.1, 81.0, 155.5, 210.3; IR (film) cm−1: 2977, 2937, 1705, 1701, 1698, 1472, 1455, 1434, 1365, 1356, 1274, 1237; MS (Cl) m/z 284.1845 (284.1860 calcd for C15H25NO4, MH). Anal. Calcd for C15H25NO4: C, 63.58; H,8.89; N, 4.94. Found: C, 63.38; H, 8.87; N, 4.88.12. The enantiomeric excess of the product is >96%. This was determined by treating a sample of the ketone with sodium borohydride/methanol (NaBH4/MeOH) (23°C) and separating the resulting 3:2 mixture of alcohol diastereomers by flash chromatography (silica gel, 2:3 ethyl acetate-hexane). The major alcohol diastereomer wasconverted to its Mosher ester4 [2.5 eq of (+)-α-methoxytrifluoromethylphenylacetic acid, 3 eq of dicyclohexylcarbodiimide, and 0.2 eq of 4-(dimethylamino)pyridine, CH2Cl2] and the crude esterification reaction mixture was analyzed using 500 MHz 1H NMR. None of the minor diastereomer was observed while doping experiments established that 2% would have been detected [diagnostic signals: δ 1.80 (δ, J = 13.4, major ester diastereomer); δ 1.82 (δ, J = 14.1, minor ester diastereomer)].Waste Disposal InformationAll toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.3. DiscussionThis procedure illustrates a fundamentally new method for constructing substituted tetrahydrofurans.5,6,7,8,9,10 This practical method assembles the tetrahydrofuran ring from allylic diol and carbonyl components and in the process forms three ring bonds: C(2)-C(3), C(4)-C(5) and O-C(5). Both aldehydes (eq 1) and ketones (illustrated in the present procedure) can be employed as the carbonyl component. Although it is often convenient to isolate the acetal intermediate, conversion to the 3-acyltetrahydrofuran can also be accomplished in many cases by the direct reaction of the diol and carbonyl components.8 High cis stereoselectivity (at least 20:1) is observed in the preparation of tetrahydrofurans that contain single side chains at carbons 2 and 5 (eq. 1). The kinetically controlled product also has the cis relationship of these side chains and the 3-acyl substituent.A definitive feature of this highly stereoselective new route to substituted tetrahydrofurans is that both syn and anti allylic diol stereoisomers typically afford identical tetrahydrofuran products. Thus, there is no need for stereoselective construction of the allylic diol reaction partner. The construction of substituted tetrahydrofurans in high enantiomeric purity from non-racemic allylic diol precursors has also been established.5,7 The rearrangement illustrated in eq. 2 is the key step in a recent synthesis of (+)-muscarine.The scope and mechanism of the SnCl4-promoted rearrangement of allylic acetals have been investigated in detail and these studies provide considerable guidance for using this new tetrahydrofuran synthesis.5,6,7,8,9 Three major limitations emerge from studies conducted to date: (1) When the tetrahydrofuran construction involves a ketone, and thus forms a quaternary center at C(5), allylic diols with alkene substituents more nucleophilic than terminal vinyl rearrange in highest yield. (2) Allylic acetals that are reluctant to ring open in the presence of acid catalysts to generate oxocarbenium ions often undergo decomposition, rather than conversion to acyltetrahydrofuran products. (3) Allylic acetals that form highly stabilized oxocarbeniums (e.g., cinnamaldehyde-derived acetals) do not undergo conversion to 3-acyltetrahydrofurans.This procedure illustrates the asymmetric synthesis of a spirobicyclic tetrahydrofuran from the reaction of readily available (S)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-butanone2 with cyclic ketones. The specific example describedargon (7440-37-1)sodium borohydride (16940-66-2)dicyclohexylcarbodiimide (538-75-0)tributylamine (102-82-9)trifluoroacetic anhydride (407-25-0)p-toluenesulfonic acid (104-15-4)ethyl acetate-hexane (2639-63-6)acetal carbon (463-57-0)Tetrabutylammonium fluoride (429-41-4)2-Bromopropene (557-93-7)4-(dimethylamino)pyridine (1122-58-3)tert-Butyllithium (594-19-4)(+)-α-methoxytrifluoromethylphenylacetic acid (56135-03-6)(2S,3S)-3-Acetyl-8-carboethoxy-2,3-dimethyl-1-oxa-8-azaspiro[4.5]decane (155534-75-1) 3-(S)-[(tert-Butyldiphenylsilyl)oxy]-2-butanone,(S)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-butanone (135367-18-9)tert-butyldiphenylsilyl1-Carbethoxy-4-piperidone (29976-53-2)isobutyraldehyde acetal3-methyl-4-pentene-2,3-diolCopyright © 1921-2007, Organic Syntheses, Inc. All Rights Reserved。

经典化学合成反应标准操作氰基转化为酯和酰胺目录1．前言 (2)2．氰基转化为酯 (2)3．氰基转化为酰胺 (2)3.1丙稀酰胺的合成 (2)3.2苯乙酰胺的合成 (3)6. 从氰基合成酰胺6.1氰基水解腈加水可以分解为伯酰胺。

由于伯酰胺会继续水解为羧酸，一般要控制水解的条件。

目前有许多方法报道，有时需要根据底物的特性选择酸性，碱性或中性的水解条件。

作为中性的条件，也有文献报道使用镍或钯催化剂的方法。

在酸性条件下与饱和碳相连的氰基，可以在酸中很方便的水解转化为酰胺，并在条件较为剧烈时，很容易进一步水解成酸。

但乙烯基或芳基腈的水解条件则要求剧烈得多，一般需要强酸条件，而且一般不会进一步水解。

在碱性条件下，利用过氧化氢氧化的方法可在室温下短时间内水解腈为伯酰胺，这是一个较为可靠的方法。

利用NaOH(aq.)-CH2Cl2相转移催化体系，DMSO-K2CO3体系[2]可以用于各种腈水解为伯酰胺。

6.1.1 盐酸水解腈为伯酰胺示例[3]HCl, H2OCN CONH2In a 3-l. three-necked round-bottomed flask equipped with glass joints are placed 200 g. (1.71 moles) of benzyl cyanide and 800 ml. of 35% hydrochloric acid. The flask is fitted with a reflux condenser, a thermometer, and an efficient mechanical stirrer. At a bath temperature of about 40° the mixture is stirred vigorously. Within a period of 20–40 minutes the benzyl cyanide goes into solution. During this time, the temperature of the reaction mixture rises about 10°above that of the bath. The homogeneous solution is kept in the bath with, or without, stirring for an additional 20–30 minutes. The warm water in the bath is replaced by tap water at about 15–20°, and the thermometer is replaced by a dropping funnel from which 800 ml. of cold distilled water is added with stirring. After the addition of about 100–150 ml., crystals begin to separate. When the total amount of water has been added, the mixture is cooled externally with ice water for about 30 minutes. The cooled mixture is filtered by suction. Crude phenylacetamide remains on the filter and is washed with two 100-ml. portions of water. The crystals are then dried at 50–80°. The yield of crude phenylacetamide is 190–200 g. (82–86%).6.1.2 浓硫酸水解不饱和腈为伯酰胺示例[4]CN CONH 21. H 2SO 42. NH 3To 106 g of 84 % sulfuric acid, was added 50 g of acrylonitrile. After stirring for 30 min at r.t., the resulting mixture was heated to 95 ℃, and stirred for 2 h. After cooling, the solid was collected by suction, and the filter cake was transferred into a beaker. To the ice-cooled solid, was added aq. ammonia with the speed that keep the temperature less than 50℃. The precipitated ammonium sulphate was filtered off, and the filtrate was cooled. The precipitate was collected by filtration, and the filter cake was washed by water, dried in vacuum to give the desired product.6.1.3 H 2O 2-K 2CO 3-DMSO 体系水解腈为伯酰胺示例[1] Cl CN30% H 2O 2, K 2CO 3DMSO, rt, 5 min ClONH 2To a stirred solution of 4-chlorobenzonitrile (1.37 g, 0.01 mol) in DMSO (3 ml), cooled in a ice bath, was added 30% H 2O 2 (1.2 ml) and K 2CO 3, the reaction was allowed to warm up to r.t. (strong exothermic effect was observed). After 5 min., distilled water (50 ml) was added, cooling applied, and the product was collected by filtration, yield 85%.6.1.4 NaOH(aq.)-CH 2Cl 2相转移催化体系水解腈为伯酰胺[2] CN (n -C 4H 9)N +HSO 4-30 % H O , CH Cl NH 2OTo a magnetically stirred dichloromethane solution (1.5 ml) of o -tolunitrile (0.5 g, 4.27 mmol) cooled in an ice ba th, are added 30% hydrogen peroxide (2.0 ml), tetrabutylammonium hydrogen sulfate (0.290 g, 0.85 mmol), and a 20% aqueous solution of sodium hydroxide (1.6 ml). Thereaction mixture is allowed to warm up to r.t. and maintained under stirring. After 1.6 h, dichloromethane is added, the organic layer is separated, washed with brine, and dried with sodium sulphate. The solvent is removed under reduced pressure to leave a white solid from which pu re o-toluamide is obtained by chromatography on silica gel. Yield 0.485 g (97%).6.2 Ritter反应碳正离子加成到腈基的氮原子上生成的腈盐加水分解得到相应的酰胺加水可以分解为酰胺。

Organic Syntheses, Coll. Vol. 4, p.755 (1963); Vol. 33, p.68 (1953).4-PENTYN-1-OLSubmitted by E. R. H. Jones, Geoffrey Eglinton, and M. C. Whiting 1.Checked by Arthur C. Cope and Ronald M. Pike. 1. ProcedureCaution! This preparation should be conducted in a hood to avoid exposure to ammonia .A solution of sodium amide in liquid ammonia is prepared according to a procedure previously described (Note 1) in a 3-l. three-necked round-bottomed flask equipped with a cold-finger condenser (cooled with Dry Ice) attached through a soda-lime tower to a gas-absorption trap,2 a mercury-sealed stirrer, and an inlet tube. Anhydrous liquid ammonia (1 l.) is introduced from a commercial cylinder through the inlet tube, and 1 g. of hydrated ferric nitrate is added, followed by 80.5 g. (3.5 g. atoms) of clean, freshly cut sodium (Note 1) and (Note 2). The inlet tube is replaced with a 250-ml. dropping funnel, and the mixture is stirred until all the sodium is converted into sodium amide , after which 120.5 g. (1 mole) of tetrahydrofurfuryl chloride 3 (Note 3) is added over a period of 25 to 30 minutes. The mixture is stirred for an additional period of 1 hour, after which 177 g. (3.3 moles) of solid ammonium chloride is added in portions at a rate that permits control of the exothermic reaction. The flask is allowed to stand overnight in the hood while the ammonia evaporates. The residue is extracted thoroughly with ten 250-ml. portions of ether , which are decanted through a Büchner funnel (Note 4). The ether is distilled, and the residue is fractionated at a reflux ratio of about 5 to 1, through a column containing a 20-cm. section packed with glass helices yielding 63–71 g. (75–85%) of 4-pentyn-1-ol , b.p. 70–71° /29 mm., n D1.4443 (Note 5).2. Notes1. Procedures for converting sodium to sodium amide are given on p. 763 and in a previous volume.42. More liquid ammonia should be added through the inlet tube if vaporization reduces the liquid volume to less than 750 ml.3. Freshly distilled tetrahydrofurfuryl alcohol should be used in the preparation of tetrahydrofurfuryl chloride according to the procedure of Organic Syntheses.34. Ether extraction of the solid must be thorough or the yield will be reduced. A large Soxhlet extractor may be used if desired.5. Others have reported b.p. 154–155°, n D 1.4432;5 b.p. 154–155°, n D 1.4450.6 A sample purified through the silver derivative had b.p. 77° /37 mm., n D 1.4464. The α-naphthylurethan of 4-pentyn-1-ol crystallized as needles from 60–80° petroleum ether; m.p. 79–80°. 3. Discussion4-Pentyn-1-ol has been prepared from 4-penten-1-ol 3 by bromination followed by dehydrobromination with alkali;6 by the reaction of 3-bromodihydropyran or 3,4-dihydro-2H-pyran with n -butylsodium , n -butyllithium , or n -butylpotassium ;5,7 by the reaction of dihydropyran or 2-methylenetetrahydrofuran with n -amylsodium or n -butyllithium ;7 by the reduction of ethyl 4-pentynoate with lithium aluminum hydride ;8and by the method used in this preparation.9251922.515References and Notes1.Victoria University of Manchester, Manchester, England.. Syntheses Coll. Vol.2, 4 (1943).. Syntheses Coll. Vol.3, 698 (1955).. Syntheses Coll. Vol.3, 219 (1955).5.Paul and Tchelitcheff, Compt. rend., 230, 1473 (1950); Paul, Angew. Chem., 63, 304 (1951);Paul, Bull. soc. chim. France, 18, 109 (1951).6.Lespieau, Compt. rend., 194, 287 (1932).7.Paul and Tchelitcheff, Bull. soc. chim. France, 19, 808 (1952).8.Colonge and Gelin, Bull. soc. chim. France, 1954, 799.9.Eglinton, Jones, and Whiting, J. Chem. Soc., 1952, 2873.AppendixChemical Abstracts Nomenclature (Collective Index Number);(Registry Number)petroleum etherα-naphthylurethan of 4-pentyn-1-olammonia (7664-41-7)ether (60-29-7)ammonium chloride (12125-02-9)sodium (13966-32-0)tetrahydrofurfuryl alcohol (97-99-4)sodium amide (7782-92-5)n-butyllithium (109-72-8)ferric nitratelithium aluminum hydride (16853-85-3)dihydropyran2-methylenetetrahydrofurann-amylsodium4-Penten-1-ol (821-09-0)Tetrahydrofurfuryl chloride(3003-84-7)4-Pentyn-1-ol (5390-04-5)3-bromodihydropyran3,4-dihydro-2H-pyran (110-87-2)ethyl 4-pentynoate (63093-41-4)n-butylsodiumn-butylpotassium Copyright © 1921-2005, Organic Syntheses, Inc. All Rights Reserved。

•蓝色：碳正离子被水或其他亲核试剂捕获,最终生成1,3-加成物〔6〕. •黑色：碳正离子的邻位碳质子被夺取,从而发生消除,生成不饱和化合物〔7〕.当原料烯烃有未取代烯碳时,其与羰基化合物的加成以与其后的消
除步骤可以协同进行,烯丙位的氢经羰基-ene反应而转变为产物中的羟基氢.
•绿色：碳正离子被另一分子羰基化合物所捕获,经正离子中间体〔8〕〔其中正电荷分散在氧和碳原子上〕,再关环,去质子化,得到最终产物二氧六环〔10〕.此路线的一个例子是从苯乙烯合成4-苯基-1,3-二氧六环.[4]•灰色：特定条件下,非常稳定的碳正离子中间体可以发生分子内环化产生恶丁环衍生物〔12〕,类似于Paterno-Büchi 光化学反应.
Prins, Chemisch Weekblad, 16, 64, 1072, 1510 1919
2.^Chemical Abstracts 13, 3155 1919。

Organic Syntheses, Coll. Vol. 4, p.261 (1963); Vol. 34, p.26 (1954).DI-tert -BUTYL MALONATE[Malonic acid, di-t -butyl ester ][I. ISOBUTYLENE METHOD]Submitted by Allen L. McCloskey, Gunther S. Fonken, Rudolph W. Kluiber, and William S. Johnson 1.Checked by James Cason, Gerhard J. Fonken, and William G. Dauben.1. ProcedureA 500-ml. Pyrex heavy-walled narrow-mouthed pressure bottle is charged with 100 ml. of ether (Note 1), 5 ml. of concentrated sulfuric acid , 50.0 g. (0.48 mole) of malonic acid , and approximately 120 ml. (about 1.5 moles) of isobutylene (Note 2), which is liquefied by passage into a large test tube immersed in a Dry Ice-acetone bath. The bottle is closed with a rubber stopper which is clamped or wired securely in place (Note 3) and is shaken mechanically at room temperature until the suspended malonic acid dissolves (Note 4). The bottle is chilled in an ice-salt bath and opened; then the contents are poured into a separatory funnel containing 250 ml. of water, 70 g. of sodium hydroxide , and 250 g. of ice. The mixture is shaken (carefully at first), the layers are separated, and the aqueous portion is extracted with two 75-ml. portions of ether . The organic layers are combined, dried over anhydrous potassium carbonate , and filtered into a dropping funnel attached to the neck of a 125-ml. modified Claisen flask (Note 5). The flask is immersed in an oil bath at about 100°, and the excess isobutylene and ether are removed by flash distillation effected by allowing the solution to run in slowly from the dropping funnel. The dropping funnel is then removed, and the residue is distilled at reduced pressure. The fraction boiling at 112–115°/31 mm. is collected. The yield of colorless di-tert -butyl malonate is60.0–62.0 g. (58–60%), n 25 1.4158–1.4161, freezing point −5.9 to −6.1° (Note 6) and (Note 7). 2. Notes1. Increase in the concentrations of reactants and product by elimination of the solvent shifts the equilibrium to the right and thus increases the yield of ester. In several runs by the checkers in which the described procedure was followed except that ether was omitted, isobutylene was increased to 240 ml. (3 moles), and shaking was continued for 12–15 hours to effect solution, yields of 88–91% were obtained. When ether was used as solvent, the larger amount of isobutylene raised the yield to only 73%. The submitters, however, have found that in the procedure without solvent the yield is more variable (in the range 69–92%), complete solution of the acid sometimes fails to occur, and in runs requiring long shaking for complete solution there is formed a lower-boiling substance the separation of which requires fractional distillation. Without solvent, there is usually an exothermic reaction as the mixture warms up. In the size run described this is no disadvantage, but in larger runs the heat evolved might be sufficient to cause the reaction to get out of control.2. Technical grade isobutylene supplied by the Matheson Company was used.3. The pressure during reaction on this scale does not exceed 40 p.s.i.4. Solution is usually complete within 6 hours, but sometimes as long as 12 hours may be required.5. The flask should be carefully washed with alkali before rinsing and drying, to ensure the removal of traces of acid which will catalyze the decomposition of the ester on warming to give isobutylene , carbon dioxide , and acetic acid . Once this decomposition begins, as evidenced by severe foaming, it is auto-catalyzed (by the acetic acid formed) and cannot be prevented from continuing at an accelerated rateexcept by rewashing the product and apparatus with alkali. The addition of some solid potassiumDcarbonate or magnesium oxide before distillation has been used with some tert -butyl esters to aid in inhibiting incipient decomposition. This treatment, however, does not appear to be necessary in the present preparation. 6. This preparation has been carried out by H. C. Dehm on a larger scale. From 150 g. of malonic acid , 200 ml. of ether , 10 ml. of concentrated sulfuric acid , and 375 ml. of isobutylene , there was obtained after shaking for 22 hours in a 1-l. bottle 201.3 g. (64% yield) of ester, n D 1.4161. 7. Other esters that have been prepared by this general procedure are: tert -butyl acetate , 50% yield, b.p. 94–97°/738 mm., n D 1.3820; tert -butyl chloroacetate , 63% yield, b.p. 56–57°/16–17 mm., n D 1.4204–1.4210 (carried out by R. C. Hunt); tert -butyl bromoacetate , 65% yield, b.p. 74–76°/25 mm., n D 1.4162; tert -butyl α-chloropropionate , yield 63%, b.p. 52–53°/12 mm., n D 1.4163 (carried out by J. S. Belew); tert -butyl o -benzoylbenzoate , 70% yield, m.p. 65–69°; di-tert -butyl succinate (dioxane was used instead of ether as solvent), 52% yield, b.p. 105–107°/7 mm., m.p. 31.5–35°; di-tert -butyl glutarate , 60% yield, b.p. 113–119°/9 mm., n D 1.4215; di-tert -butyl β,β-dimethylglutarate , 67% yield, b.p. 72–75°/1 mm., n D 1.4246.[II. ACID CHLORIDE METHOD]Submitted by Chittaranjan Raha 2Checked by William S. Johnson and Rudolph W. Kluiber. 1. ProcedureA. Malonyl dichloride . In a 250-ml. Erlenmeyer flask (Note 1) fitted by a ground-glass joint to areflux condenser capped with a calcium chloride drying tube are placed 52 g. (0.5 mole) of finely powered, dry malonic acid (Note 2) and 120 ml. (about 1.65 mole) of thionyl chloride (Note 3). The flask is warmed for 3 days in a heating bath kept at 45–50° (Note 4). During this period the mixture, which is agitated occasionally by gentle swirling, gradually darkens to a deep brownish red or sometimes a blue color. Finally the mixture is heated at 60° for 5–6 hours. After cooling, it is transferred to a 125-ml. modified Claisen flask and distilled at reduced pressure (water aspirator). A calcium chloride guard tube is inserted between the vacuum line and the apparatus, and the flask is heated with a bath rather than a free flame. After a small fore-run of thionyl chloride , the malonyl chloride distils at 58–60°/28 mm. The pale yellow product amounts to 50.5–60 g. (72–85% yield), n D1.4572. B. Di-tert-butyl malonate . A 1-l. three-necked flask is fitted with a thermometer, a mercury- or rubber sleeve-sealed mechanical stirrer, a reflux condenser protected by a calcium chloride guard tube, and a dropping funnel (either pressure-equalized or protected by a calcium chloride guard tube). A mixture of 100 ml. (about 1 mole) of tert -butyl alcohol , dried by distillation from sodium (p. 134, Note 2), and 80 ml. (0.63 mole) of dry dimethylaniline (Note 5) is placed in the flask, the stirrer is started, and a solution of 28.0 g. (0.2 mole) of malonyl dichloride in about 60 ml. of dry, alcohol-free chloroform (Note 6) is added slowly from the dropping funnel while the reaction flask is cooled in an ice bath. The reaction is strongly exothermic, and the rate of dropping is regulated so that the temperature of the mixture does not exceed 30°. After the addition is complete (about 30 minutes) the light-greenish mixture is heated under reflux for 4 hours. The mixture is then cooled, 150 ml. of ice-cold 6N sulfuric acid is added with stirring, and the product is extracted with three 250-ml. portions of ether (Note 7). The combined ether extracts are washed once with 6N sulfuric acid , twice with water, twice24.225252525252529with 10% potassium carbonate, and once with saturated sodium chloride, and are finally dried over anhydrous sodium sulfate to which a small amount of potassium carbonate is added. The ether is removed by distillation at reduced pressure (water aspirator), and the residue (to which a pinch of magnesium oxide is added) is distilled at reduced pressure from a modified Claisen flask (Note 8). The yield of colorless di-tert-butyl malonate, distilling at 65–67°/1 mm., 110–111°/22 mm., is 35.8–36.2 g.251.4159, m.p. about −6°.(83–84%), nD2. Notes1. Better results are obtained by using a flat-bottomed flask, which permits the insoluble malonic acid to be distributed over a greater surface.2. The reaction mixture is heterogeneous at first, and if the acid is not finely powdered, some of it remains unreacted. Attempts to carry out the reaction on a larger scale resulted in some charring and lower yields.3. Eastman Kodak Company white label quality thionyl chloride is satisfactory.4. The temperature range is critical, and yields are lower if it is not controlled carefully. The use of pyridine as a catalyst is not recommended as it produces charring even after relatively short reaction periods.5. J. T. Baker dimethylaniline (purified grade) is satisfactory without distillation.6. The chloroform was dried over and distilled from anhydrous calcium chloride just before use.7. The dimethylaniline may be recovered from the aqueous layer where it is dissolved as the salt.8. Di-tert-butyl malonate, like most tert-butyl esters, decomposes readily on heating in the presence of traces of acids. It is therefore desirable to give all glassware to be used for distillation of the material an alkali rinse before use. The addition of a small amount of magnesium oxide also helps to inhibit the decomposition during distillation.3 When decomposition starts, foaming is generally observed. In this event the addition of glass wool to the distillation flask helps to keep the product from foaming over.3. DiscussionProcedure I is a modification3 of the method of Altschul4 for preparing tert-butyl esters. Di-tert-butyl malonate also has been prepared by the reaction of malonyl dichloride and tert-butyl alcohol in the presence of a base,5,6, and by the reaction of carbon suboxide with tert-butyl alcohol.7 Procedure II is based on the former5 method and developed from studies initiated by P. C. Mukharji of the University College of Science and Technology, Calcutta.Malonyl dichloride has been prepared from malonic acid and thionyl chloride,5,8,9,10,11,12 and from carbon suboxide and anhydrous hydrogen chloride.13 The present procedure is adapted from that of Staudinger and Bereza10 and of Backer and Homan.5This preparation is referenced from:z Org. Syn. Coll. Vol. 4, 417z Org. Syn. Coll. Vol. 6, 414z Org. Syn. Coll. Vol. 7, 142References and Notes1.University of Wisconsin, Madison, Wisconsin.2.Rose Research Institute, Calcutta, India.3.Fonken and Johnson, J. Am. Chem. Soc., 74, 831 (1952).4.Altschul, J. Am. Chem. Soc., 68, 2605 (1946).5.Backer and Homan, Rec. trav. chim., 58, 1048 (1939).6.Backer and Lolkema, Rec. trav. chim., 57, 1234 (1938).7.Hagelloch and Feess, Chem. Ber., 84, 730 (1951).8.Auger, Ann. chim. et phys., [6] 22, 347 (1891).9.Asher, Ber., 30, 1023 (1897).10.Staudinger and Bereza, Ber., 41, 4463 (1908).11.von Auwers and Schmidt, Ber., 46, 477 (1913).12.McMaster and Ahmann, J. Am. Chem. Soc., 50, 145 (1928).13.Diels and Wolf, Ber., 39, 696 (1906).AppendixChemical Abstracts Nomenclature (Collective Index Number);(Registry Number)carbon suboxidecalcium chloride (10043-52-4)potassium carbonate (584-08-7)sulfuric acid (7664-93-9)hydrogen chloride (7647-01-0)acetic acid (64-19-7)ether (60-29-7)sodium hydroxide (1310-73-2)thionyl chloride (7719-09-7)chloroform (67-66-3)sodium chloride (7647-14-5)sodium sulfate (7757-82-6)carbon dioxide (124-38-9)pyridine (110-86-1)sodium (13966-32-0)dimethylaniline (121-69-7)Malonyl dichloride (1663-67-8)Malonic acid (141-82-2)dioxane (5703-46-8)magnesium oxideisobutylene (9003-27-4)tert-butyl alcohol (75-65-0)tert-Butyl acetate (540-88-5)tert-Butyl chloroacetate (107-59-5)Di-tert-butyl malonate,Malonic acid, di-t-butyl ester (541-16-2)tert-butyl bromoacetate (5292-43-3)tert-butyl α-chloropropionate (40058-88-6)tert-butyl o-benzoylbenzoatedi-tert-butyl succinate (926-26-1)di-tert-butyl glutarate (43052-39-7)di-tert-butyl β,β-dimethylglutarate Copyright © 1921-2005, Organic Syntheses, Inc. All Rights Reserved。

Organic Syntheses, Coll. Vol. 10, p.613 (2004); Vol. 76, p.86 (1999).(2S,3S)-(+)-(3-PHENYLCYCLOPROPYL)METHANOL[ Cyclopropanemethanol, 2-phenyl-, (1S-trans)- ]Submitted by André B. Charette and Hélène Lebel1 .Checked by Kevin Minbiole, Patrick Verhoest, and Amos B. Smith, III.1. ProcedureA.Butylmagnesium bromide. To a 500-mL, three-necked, round-bottomed flask equipped with an egg-shaped magnetic stirrer, 125-mL pressure-equalizing addition funnel, reflux condenser and a glass stopper (Note 1), is added 17.0 g (0.70 mol) of magnesium turnings(Note 2). Stirring is started, and the system is flame-dried for 2 min. The flask is cooled to room temperature under a flow of argon, and 30 mL of ether(Note 3) is introduced to cover the magnesium. A solution of 24 mL (0.22 mol) of bromobutane(Note 4) in 70 mL of ether is placed in the pressure-equalizing addition funnel. Then, 1 mL (0.01 mol) of bromobutane is added to the suspension of magnesium in ether. The mixture is heated gently to initiate the reaction (Note 5). When the reaction has started, the solution of bromide in ether is added dropwise at a rate sufficient to maintain a gentle reflux (Note 6). After completion of the addition, the funnel is rinsed with 5 mL of ether . The gray solution is stirred for 15 min and then transferred to a dry flask under argon via cannula. The Grignard reagent is titrated with a solution of isopropyl alcohol in benzene using 1,10-phenanthroline as the indicator (Note 7).2 A 1.90-2.10 M solution of Grignard reagent is obtained.B.Butylboronic acid. To a 1-L, one-necked, round-bottomed flask equipped with an egg-shaped magnetic stirrer (Note 1) and an internal thermocouple probe (Note 11) is added 220 mL of ether(Note 3), followed by 10 mL (89.2 mmol) of trimethyl borate(Note 12). The clear solution is cooled to −75°C (internal temperature) and stirred vigorously, then 45 mL (87.8 mmol) of a 1.95 M solution of butylmagnesium bromide in ether(Note 13) is added dropwise via cannula at such a rate that the internal temperature does not exceed −65°C (Note 14). After the addition is complete, the resulting white slurry is stirred for an additional 2 hr at −75°C under argon. The cooling bath is removed, and thereaction mixture is allowed to warm to room temperature (Note 15). Hydrolysis is carried out by the dropwise addition of 100 mL of an aqueous 10% solution of hydrochloric acid . The white precipitate is dissolved, and the resulting clear biphasic mixture is stirred for 15 min, at which time the two layers are separated. The aqueous layer is extracted with ether (2 × 50 mL), and the combined extracts are dried over magnesium sulfate . After concentration of the ethereal solution under reduced pressure, the residual white solid is purified by recrystallization as follows: After dissolution in hot water (25 mL), the resulting biphasic solution is cooled to 0°C to induce recrystallization of the boronic acid. The solid is collected on a Büchner funnel, washed with 50 mL of hexanes and placed under vacuum (0.2 mm) for 60 min (Note 16) and (Note 17). Between 5.0-6.5 g (55-72% yield) of the boronic acid is produced as a white solid (Note 18).C.[(2-)-N,O,O'[2,2'-Iminobis[ethanolato]]]-2-butylboron,1. A 250-mL, one-necked, round-bottomed flask equipped with an egg-shaped magnetic stirrer (Note 1) is charged with 5.15 g (50.5 mmol) of butylboronic acid and 5.31 g (50.5 mmol) of diethanolamine(Note 19). Ether, 100 mL (Note 3) and 50 mL of dichloromethane(Note 20) are added, followed by about 10 g of molecular sieves 3Å (Note 21). The resulting heterogeneous solution (Note 22) is stirred for 2 hr under argon. The solid is triturated with dichloromethane (50 mL), filtered through a medium fritted disk funnel and washed with dichloromethane (2 × 50 mL). The filtrate is concentrated under reduced pressure to produce the crude desired complex. The diethanolamine complex is purified by recrystallization as follows: the white solid is dissolved in hot dichloromethane (20 mL), then ether (50 mL) is added to induce recrystallization of the complex. The mixture is cooled to 0°C and the solid is collected on a Büchner funnel and washed with ether (2 × 30 mL). The product is dried under reduced pressure (0.2 mm) to afford 7.70 g (89%) of the title compound as a white crystalline solid (Note 23).D.(4R-trans)-2-Butyl-N,N,N',N'-tetramethyl[1,3,2]dioxaborolane-4,5-dicarboxamide3. A 500-mL, one-necked, round-bottomed flask equipped with an egg-shaped magnetic stirrer, under argon is charged with 7.70 g (45.0 mmol) of the butylboronate diethanolamine complex and 11.9 g (58.3 mmol) of (R,R)-(+)-N,N,N',N'-tetramethyltartaric acid diamide(Note 24). The solids dissolve upon the addition of 225 mL of dichloromethane . Brine (70 mL) is added, and the resulting biphasic solution is stirred for 30 min under argon. The two layers are separated, and the aqueous layer is extracted with dichloromethane (50 mL). The combined organic layers are washed with brine (50 mL), dried over magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure and dried under reduced pressure (0.2 mm) to give 11.3 g (93%) of the title compound as a pale yellow oil (Note 25).E.(2S,3S)-(+)-(3-Phenylcyclopropyl)methanol. A 250-mL, one-necked, round-bottomed flask equipped with an egg-shaped magnetic stirrer (Note 26) and an internal thermocouple probe (Note 11), is charged with 45 mL of dichloromethane(Note 20) and 1.60 mL (14.9 mmol) of 1,2-dimethoxyethane (DME) (Note 27). The solution is cooled to −10°C (internal temperature) with an acetone/ice bath, and 1.50 mL (14.9 mmol) of diethylzinc is added (Note 28). To this stirred solution is added 2.40 mL (29.8 mmol) of diiodomethane(Note 29) over a 15-20 min period while maintaining the internal temperature between −8°C and −12°C. After the addition is complete, the resulting clear solution is stirred for 10 min at −10°C. A solution of 2.41 g (8.94 mmol) of the dioxaborolane ligand in 10 mL of dichloromethane is added via cannula under argon over a 5-6 min period while maintaining the internal temperature below −5°C. A solution of 1.00 g (7.45 mmol) of cinnamyl alcohol(Note 30) in 10 mL of dichloromethane is immediately added via cannula under argon over a 5-6 min period while maintaining the internal temperature under −5°C. The cooling bath is removed, and the reaction mixture is allowed to warm to room temperature and stirred for 8 hr at that temperature (Note 31).Workup.Method A. The reaction is quenched with aqueous saturated ammonium chloride (10 mL) and aqueous 10% hydrochloric acid (40 mL). The mixture is then diluted with ether (60 mL) and transferred to a separatory funnel. The reaction flask is rinsed with ether (15 mL), and aqueous 10% hydrochloric acid (10 mL) and both solutions are transferred to the separatory funnel. The two layers are separated, and the aqueous layer is washed with ether (20 mL). The combined organic layers are transferred to an Erlenmeyer flask, and a solution containing 60 mL of aqueous 2 N sodium hydroxide and 10 mL of aqueous 30% hydrogen peroxide is added in one portion (Note 32). The resulting biphasic solution is stirred vigorously for 5 min. The two layers are separated and the organic layer is washed successively with aqueous 10% hydrochloric acid(50 mL), aqueous saturated sodium sulfite(50 mL),aqueous saturated sodium bicarbonate (50 mL), and brine (50 mL). The organic layer is dried over magnesium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The crude product is left under reduced pressure (0.2 mm) overnight (12-16 hr) to remove the butanol produced in this oxidative work-up. The product is purified by a Kugelrohr distillation (90°C, 0.8 mm) to afford 1.05 g (95%) of (2S,3S)-(+)-(3-phenylcyclopropyl)methanol as a colorless oil (Note 33) and (Note 34). Workup . Method B [with recovery of (R,R)-(+)-N,N,N',N'-tetramethyltartaric acid diamide ]. The mixture is quenched with aqueous saturated ammonium chloride (80 mL), and the resulting biphasic mixture is stirred for 5 min. The two clear layers are separated, and the aqueous layer is washed with dichloromethane (20 mL) (Note 35). The combined organic layers are dried over magnesium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The residual oil is dissolved in ether (75 mL) and water (50 mL). The resulting biphasic mixture is stirred for 1 hr. The layers are separated, and the aqueous layer is washed with ether (20 mL). This aqueous layer is kept for tetramethyltartaric acid diamide recovery (see below). The combined organic layers are treated with 60 mL of aqueous 2 N sodium hydroxide and 10 mL of aqueous 30% hydrogen peroxide (Note 32). The resulting biphasic mixture is stirred for 5 min. The two layers are separated and the organic layer is washed successively with aqueous 10% hydrochloric acid (50 mL), saturated aqueous sodium sulfite (50 mL), saturated aqueous sodium bicarbonate (50 mL), and brine (50 mL). The organic layer is dried over magnesium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The crude product is left under reduced pressure (0.2 mm) overnight (12-16 hr) to remove butanol produced in this oxidative work-up. The product is purified by a Kugelrohr distillation (90°C, 0.8 mm) to afford 1.02 g (93%) of (2S ,3S )-(+)-(3-phenylcyclopropyl)methanol as a colorless oil.Recovery of (R,R)-(+)-N,N,N',N'-tetramethyltartaric acid diamide . The aqueous layer from the above extraction is concentrated under reduced pressure, and the crude product is recrystallized by an initial dissolution in hot dichloromethane (5 mL) followed by the addition of ethyl acetate (10 mL) to afford between 600 mg to 750 mg (33-41% yield) of the (R,R)-(+)-N,N,N',N'-tetramethyltartaric acid diamide (Note 36) and (Note 37).2. Notes1. All glassware was dried in an oven (110°C) and after assembly was allowed to cool under an atmosphere of argon .2. Magnesium turnings were purchased from Sigma-Aldrich Fine Chemicals Company Inc. and were used without further purification.3. Ether was freshly distilled from sodium/benzophenone.4. Bromobutane was purchased from Fisher Scientific Company and was freshly distilled from phosphorus pentoxide (P 2O 5) (bp 100-104°C).5. The formation of a gray cloudy suspension indicates that the reaction has started. Furthermore, the reaction is sufficiently exothermic to induce the ether to reflux even when the reaction flask is not heated. If the reaction does not start within 2 to 3 min, repeat the heating procedure.6. Between 1.5 hr and 2 hr are needed for addition.7. A dried 10-mL, one-necked, round-bottomed flask is charged with 1 mL of Grignard, some drops of THF (Note 8) and a crystal of 1,10-phenanthroline (Note 9). The slightly pink solution is titrated with a 0.5 M solution of isopropyl alcohol in benzene (Note 10). Between 3.8 and 4.2 mL (±0.2 mL) is obtained to give a clear colorless solution (three titrations).8. THF was freshly distilled from sodium/benzophenone.9. 1,10-Phenanthroline was purchased from Sigma-Aldrich Fine Chemicals Company Inc. and was used without further purification. 10. Isopropyl alcohol was freshly distilled from calcium hydride (CaH 2) and benzene was freshly distilled from sodium . 11. A Barnant 100, Type T Thermo-Couple Thermometer was used to monitor the internal temperature of the reaction solution. 12. Anhydrous trimethyl borate (with <5% of methanol ) was purchased from Sigma-Aldrich Fine Chemicals Company Inc. and was used without further purification. Alternatively, a non anhydrous reagent can be dried by distillation from calcium hydride (bp 68-69°C). 13. Commercially available (Sigma-Aldrich Fine Chemicals Company Inc.), butylmagnesium chloride ,2.0 M in ether , can be used and a similar yield is observed.14. Between 20 and 30 min are needed for the addition. 15. Between 1 hr and 1.5 hr are needed. 16. The amount of the boroxine significantly increases if the solid is left under reduced pressure for a longer period of time. The boroxine is always a contaminant of the boronic acid (see discussion). 17. Sometimes a second recrystallization is needed to obtain pure boronic acid by removing by-products resulting from autooxidation. 18. The physical properties are as follows: mp 95-97°C; 1H NMR (400 MHz, DMSO) δ: 0.56 (t, 2 H, J = 7.6), 0.83 (t, 3 H, J = 7.2), 1.31-1.19 (m, 4 H), 7.34 (br s, 2 H) ; 13C NMR (100 MHz, DMSO) δ: 13.9, 15.3 (br), 25.1, 26.5 ; 11B NMR (128.4 MHz, DMSO) δ: 32.7 . 19. Diethanolamine was purchased from Fisher Scientific Company and was used without further purification. 20. Dichloromethane was freshly distilled from CaH 2. 21. Molecular sieves, 3Å, powder, average particle size 3-5 μ were purchased from Sigma-Aldrich Fine Chemicals Company Inc. and dried under vacuum at 250°C for 24 hr, before using. 22. A few minutes after the addition of the molecular sieves, a white precipitate forms and sometimes maintaining stirring becomes difficult. 23. The physical properties are as follows: mp 145-148°C; 1H NMR (400 MHz, CDCl 3) δ: 0.44-0.48 (m, 2 H), 0.88 (t, 3 H, J = 7.1), 1.21-1.37 (m, 4 H), 2.79 (br s, 2 H), 3.26 (br s, 2 H), 3.88 (br s, 2 H), 3.98 (br s, 2 H),4.80-4.98 (m, 1 H) ; 13C NMR (100 MHz, CDCl 3) δ: 14.1, 18.4 (br), 26.5, 28.1, 51.4, 62.5 ; 11B NMR (128.4 MHz, CDCl 3) δ: 13.1, 32.7 . Anal. Calcd for C 8H 18BNO 2: C, 56.18; H, 10.61; N, 8.19. Found: C, 56.15; H, 10.86; N, 8.07. 24. (R,R)-(+)-N,N,N',N'-Tetramethyltartaric acid diamide was prepared from diethyl tartrate and dimethylamine and was freshly recrystallized with methanol and ethyl acetate .3 The physical properties are as follows: mp 186-187°C [lit.2 189-190°C]; 1H NMR (400 MHz, CDCl 3) δ: 3.01 (s, 6 H), 3.13 (s, 6 H), 4.21 (br s, 2 H), 4.65 (s, 2 H) ; 13C NMR (100 MHz, CDCl 3) δ: 36.1, 36.9, 69.8, 170.8 ; [α]20 D +43° (EtOH, c 2.03) [lit.2 [α]20 D +43° (EtOH, c 3.0)]. This product is also commercially available from Sigma-Aldrich Fine Chemicals Company Inc. 25. The physical properties are as follows: 1H NMR (400 MHz, CDCl 3) δ: 0.85 (t, 2 H, J = 7.7); 0.87 (t, 3 H, J = 7.2), 1.29-1.41 (m, 4 H), 2.98 (s, 6 H), 3.20 (s, 6 H), 5.53 (s, 2 H) ; 13C NMR (100 MHz, CDCl 3) δ: 9.9 (br), 13.6, 25.0, 25.7, 35.7, 36.9, 75.6, 168.23 ; 11B NMR (128.4 MHz, CDCl 3) δ: 34.2 ; [α]20 D −104.4° (CHCl 3, c 1.70). HRMS Calcd for C 12H 23BN 2O 4: 270.1751. Found: 270.1746. Anal. Calcd for C 12H 23BN 2O 4: C, 53.35; H, 8.58; N, 10.37. Found: C, 53.67; H, 9.07; N, 10.21. 26. All glassware was flame dried, then cooled under a flow of dry argon . 27. DME was freshly distilled from sodium/benzophenone. 28. Diethylzinc is a moisture sensitive and pyrophoric liquid and must be manipulated in an inert atmosphere with gas-tight syringes. Neat diethylzinc was purchased from Akzo Nobel Chemicals Company Inc. and was used without further purification. 29. Diiodomethane was purchased from Acros-Fisher Scientific Company and used without further purification. If necessary, diiodomethane can be purified if it shows any signs of slight decomposition (orange or red color develops over time): diiodomethane is washed with aqueous saturated sodium sulfite , dried over sodium sulfate (Na 2SO 4), and distilled from copper (40°C, 1.0 mm). The pale yellow liquid is collected on copper . 30. Cinnamyl alcohol was purchased from Sigma-Aldrich Fine Chemicals Company Inc. and was freshly purified by Kugelrohr distillation: a first fraction boiling at <70°C (1.0 mm) was discarded, and the alcohol was collected as a white solid at 80°C (1.0 mm). 31. A similar yield is obtained when the submitters stirred this mixture for 14 hr. No noticeable decomposition and side reactions are observed after slightly longer periods of time. 32. Hydrogen peroxide was purchased from ACP Chemicals Company Inc. and used without further purification. 33. Alternatively, the product can be purified by flash chromatography on silica gel (78.5 g, 4 cm × 16 cm) using 30% ethyl acetate in hexanes as the mobile phase (800 ml) to afford 1.06 g (96%) of the title compound. 34. The physical properties are as follows: bp 90°C, 0.8 mm; IR (film) cm −1: 3350, 3050, 3000, 2950, 2900, 1600, 1500, 1450, 1100, 1050, 1000, 750, 700 ; 1H NMR (400 MHz, CDCl 3) δ: 0.92-1.01 (m, 2 H), 1.43-1.51 (m, 1 H), 1.75 (br s, 1 H), 1.82-1.86 (m, 1 H), 3.59-3.67 (m, 2 H), 7.07-7.10 (m, 2 H),7.15-7.20 (m, 1 H), 7.25-7.30 (m, 2 H) ; 13C NMR (100 MHz, CDCl 3) δ: 13.8, 21.2, 25.2, 66.3, 125.6, 125.8, 128.3, 142.5 ; [α]20 D +82° (EtOH, c 1.74) [lit.4 (2R,3R)-cyclopropylmethanol >99% ee [α]20 D −92° (EtOH, c 1.23)]. Anal. Calcd for C 10H 12O: C, 81.04 H, 8.16. Found: C, 81.15; H, 8.30. The enantiomeric excess of the product is determined precisely by GC analylsis of the corresponding trifluoroacetate ester derivative: To a solution of 10 mg of the crude alcohol in 0.75 mL of pyridine is added 0.25 mL of trifluoroacetic anhydride (TFAA). After 30 min at room temperature, an additional 0.25 mL of TFAA is added. After 30 min, the reaction mixture is diluted with 5 mL of ether . This solution was injected directly into the GC (0.5 μL) with the following conditions: Cyclodex G-TA, 0.32 × 30 m; pressure 25 psi; isotherm: 110°C, T r (minor) 11.5 min, T r (major) 12.0 min; enantiomeric ratio: 29:1 (93% ee). 35. If the resulting organic layers are not clear, the combined organic layers should be washed with an additional 50 mL of aqueous saturated ammonium chloride . 36. An additional 10-15% of the diol can be recovered from the first aqueous saturated ammonium chloride extract (Note 38): the layer is concentrated on a rotatory evaporator and the white solid is triturated with cold methanol (30 mL), the mixture is filtered on a Büchner funnel, and the solid is washed with cold methanol (20 mL). The filtrate is concentrated to ca. 25 mL and treated with 2.5 g of sodium sulfide (Note 39). The resulting mixture is stirred for 30 min and then filtered on Celite (6 g, 1 cm × 4 cm). The filtrate is concentrated by rotary evaporation, and the residue is purified by flash chromatography on silica gel (75 g, 3.5 cm × 14.5 cm) by dissolving it in 10 mL of 10% methanol in chloroform and eluting with 10% methanol in chloroform . A recrystallization with dichloromethane and ethyl acetate give pure material. 37. The physical properties are identical to those of (Note 24). 38. The diol decomposes after a few hours at room temperature in this layer. 39. Sodium sulfide was purchased from Anachemia Science and was used without further purification.Waste Disposal InformationAll toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.3. DiscussionParts A-D. The preparation of boronic acids by the addition of a Grignard reagent to a trialkyl borate is one of the most convenient and well-established methods involving relatively inexpensive starting materials.5 6 The carefully monitored addition of butylmagnesium bromide to trimethyl borate avoids any complications resulting from overaddition, and relatively good yields of the butylboronic acid are obtained after acid hydrolysis. Usually, alkylboronic acids are relatively difficult to characterize and to obtain analytically pure,7 8 because they readily tend to form boroxines (anhydrides) under dehydrating conditions (when heated or when left under reduced pressure). The white solid (butylboronic acid ) is transformed into a colorless oil (tributylboroxine) if dehydration is pushed to completion. Conversely, butylboronic acid and its boroxine are also readily oxidized by air to generate 1-butanol and boric acid .9 10 For these reasons, it is almost impossible to isolate butylboronic acid without any traces of water, its boroxine or oxidation by-products.In order to avoid these complications, butylboronic acid is quickly converted to its air-stable and more robust diethanolamine derivative 1.11 Complex 1 could be contaminated with some unseparable diethanolamine if a small excess of diethanolamine is used in its preparation. However, this has no effect on the efficiency of the synthesis of the chiral dioxaborolane ligand 3. Diethanolamine complex 1 reacts quantitatively with a slight excess of tetramethyltartramide 2 under biphasic conditions to produce the desired chiral dioxaborolane ligand 3. Ligand 3 is relatively stable, and is neither excessively hygroscopic nor oxygen-sensitive. It must be stored under argon for longer periods of time. However, the submitters have shown that the enantioselectivities are directly related to the ligand purity.Consequently, it is generally preferable to use freshly prepared ligand for obtaining optimal results.Part E. The enantioselective cyclopropanation of allylic alcohols using the chiral dioxaborolane ligand 3 and Zn(CH 2I)2·DME is a powerful tool for synthesizing three-membered rings. This method is much simpler and produces superior enantiomeric excesses compared to those using other stoichiometric chiral ligands.12 13 14 The scope of the reaction is wide and a variety of allylic alcohols have been converted into their cyclopropane derivatives in excellent enantiomeric excesses (88-94%).15 16 It was also shown that polyenes can be cyclopropanated at the allylic alcohol position with excellent chemo- and enantioselectivities.17 Recently, this reaction has been used in the synthesis of cyclopropane containing natural products.18 19 20 21Caution! The previously reported preparation of Zn(CH 2I)2 without a complexing additive 22 is highly exothermic, and a violent decomposition sometimes occurred. For safety reasons, the use of the Zn(CH 2I)2·DME as reported here is mandatory if this reaction is carried out on a =8 mmole scale.23 If the internal temperature during the formation of the reagent is carefully monitored, the procedure reported here is extremely safe even on larger scales.Note that the structure of Zn(CH 2I)2·DME is derived from the stoichiometry of the reactants (Et 2Zn, CH 2I 2, DME). Substantial quantities of IZnCH 2I·DME are necessarily formed at the reaction temperature and as a by-product of the cyclopropanation. Another improvement was made in this procedure: the number of equivalents of the reagent has been decreased to 2.0 equiv (vs 5 equiv in the original paper). However, under these conditions that minimize the amount of Et 2Zn used but require longer reaction times, the yield of the diol recovery dropped to ca. 50%.The cyclopropanation of cinnamyl alcohol is a good example of the use of dioxaborolane ligand 3 as chiral additive to synthesize chiral cyclopropanes.References and Notes1.Departement de Chimie, Université de Montréal, P.O. Box 6128, Station Downtown, Montréal(Québec) Canada, H3C 3J7.2.Soai, K.; Machida, H.; Yokota, N. J. Chem. Soc. Perkin Trans. I 1987, 1909.3.Seebach, D.; Kalinowski, H.-O.; Langer, W.; Crass, G.; Wilka, E.-M. Org. Synth., Coll. Vol. VII1990, 41.4.Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M. J. Am. Chem. Soc. 1991, 113, 726.5.Srebnik, M.; Cole, T. E.; Ramachandran, V.; Brown, H. C. J. Org. Chem. 1989, 54, 6085;6.Washburn, R. M.; Levens, E.; Albright, C. F.; Billig, F. A. Org. Synth., Coll. Vol. IV 1963, 68and references cited therein.7.Martichonok, V.; Jones, J. B. J. Am. Chem. Soc. 1996, 118, 950;8.Mathre, D. J.; Jones, T. K.; Xavier, L. C.; Blacklock, T. J.; Reamer, R. A.; Mohan, J. J.; Jones, E.T. T.; Hoogsteen, K.; Baum, M. W.; Grabowski, E. J. J. J. Org. Chem. 1991, 56, 751. 9.Korcek, S.; Watts, G. B.; Ingold, K. U. J. Chem. Soc., Perkin Trans. 2 1972, 242;10.Johnson, J. R.; Van Campen, Jr., M. G. J. Am. Chem. Soc. 1938, 60, 121.11.Brown, H. C.; Vara Prasad, J. V. N. J. Org. Chem. 1986, 51, 4526.aji, Y.; Nishimura, M.; Fujisawa, T. Chem. Lett. 1992, 61;aji, Y.; Sada, K.; Inomata, K. Chem. Lett. 1993, 1227;14.Kitajima, H.; Aoki, Y.; Ito, K.; Katsuki, T. Chem. Lett. 1995, 1113.15.Charette, A. B.; Juteau, H. J. Am. Chem. Soc. 1994, 116, 2651;16.Charette, A. B.; Lemay J., Angew. Chem., Int. Ed. Engl. 1997, 36, 1090.17.Charette, A. B.; Juteau, H.; Lebel, H.; Deschênes, D. Tetrahedron Lett. 1996, 37, 7925.18.For selected examples, see: (a) White, J. D.; Kim, T.-S.; Nambu, M. J. Am. Chem. Soc. 1997,119, 103;19.Barrett, A. G. M.; Kasdorf, K. J. Chem. Soc., Chem. Comm. 1996, 325;20.Falck, J. R.; Mekonnen, B.; Yu, J.; Lai, J.-Y. J. Am. Chem. Soc. 1996, 118, 6096;21.Charette, A. B.; Lebel, H. J. Am. Chem. Soc. 1996, 118, 10327.22.Denmark, S. E.; Edwards, J. P. J. Org. Chem.1991, 56, 6974.23.Charette, A. B.; Prescott, S.; Brochu, C. J. Org. Chem.1995, 60, 1081.AppendixChemical Abstracts Nomenclature (Collective Index Number);(Registry Number)(2S,3S)-(+)-(3-Phenycyclopropyl)methanol:Cyclopropanemethanol, 2-phenyl-,(1S-trans)- (12); (110659-58-0)Butylmagnesium bromide:Magnesium, bromobutyl- (8,9); (693-03-8)Magnesium (8,9); (7439-95-4)1-Bromobutane:Butane, 1-bromo- (8,9); (109-65-9)Isopropyl alcohol:2-Propanol (8,9); (67-63-0)1,10-Phenanthroline (8,9); (66-71-7)Butylboronic acid:1-Butaneboronic acid (8);Boronic acid, butyl- (9); (4426-47-5)Trimethyl borate:Boric acid, trimethyl ester (8,9); (121-43-7)Diethanolamine:Ethanol, 2,2'-iminodi- (8);Ethanol, 2,2'-iminobis- (9): (111-42-2)(4R-trans)-2-Butyl-N,N,N',N'-tetramethyl[1,3,2]dioxaborolane-4,5-dicarboxamide:1,3,2-Dioxaborolane-4,5-dicarboxamide, 2-butyl-N,N,N'N'-tetramethyl-, (4R-trans)- (13); (161344-85-0)(R,R)-(+)-N,N,N',N'-Tetramethyltartaric acid diamide:Tartramide, N,N,N'N'-tetramethyl-, (+)- (8);Butanediamide, 2,3-dihydroxy-N,N,N'N'-tetramethyl-, [R-(R,R)]- (9); (26549-65-5)Dimethoxyethane:Ethane, 1,2-dimethoxy- (8,9); (110-71-4)Diethylzinc:Zinc, diethyl- (8,9); (557-20-0)Diiodomethane:Methane,diiodo-(8,9); (75-11-6)Cinnamyl alcohol (8);2-Propen-1-ol, 3-phenyl- (9); (104-54-1)Hydrogen peroxide (8,9); (7722-84-1)Sodium sulfite:Sulfurous acid, disodium salt (8,9); (7757-83-7)Copper (8,9); (7440-50-8)Trifluoroacetic anhydride:Acetic acid, trifluoro-, anhydride (8,9); (407-25-0)Sodium sulfide (8,9); (1313-82-2) Copyright © 1921-2005, Organic Syntheses, Inc. All Rights Reserved。

Organic Syntheses, Coll. Vol. 10, p.382 (2004); Vol. 75, p.31 (1998).ETHYL (R)-2-AZIDOPROPIONATE[ Propanoic acid, 2-azido-, ethyl ester, (R)- ]Submitted by Andrew S. Thompson, Frederick W. Hartner, Jr., and Edward J. J. Grabowski 1 .Checked by Christopher L. Lynch and Stephen F. Martin. 1. ProcedureEthyl (R)-2-azidopropionate . An oven-dried, 500-mL, three-necked flask is equipped with an overhead stirrer, nitrogen inlet, and an immersion thermometer (Note 1). The flask is charged with ethyl S-(−)-lactate (19.2 mL, 0.169 mol) (Note 2), tetrahydrofuran (175 mL) (Note 3), and diphenylphosphoryl azide (40 mL, 0.185 mol) (Note 4). The mixture is cooled to 2°C in an ice-water bath. To the mixture is added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (24 mL, 0.157 mol) (Note 5) dropwise via syringe. (Caution: The DBU addition causes an exotherm. The reaction temperature is maintained below 5°C by carefully controlling the rate of addition. For this reaction the addition required 35 min). A thick white precipitate forms during the DBU charge. The reaction is stirred at 1°C for 1 hr, and then it is warmed to room temperature and stirred under nitrogen for 24 hr (Note 6). The resulting homogeneous reaction is diluted with methyl tert-butyl ether (MTBE, 170 mL), and water (100 mL) is added. After the water layer is removed, the organic phase is washed with water (100 mL) and 0.5 M citric acid monohydrate (100 mL). The organic layer is dried ( Na 2SO 4 ) and concentrated under reduced pressure to ca. 40-50 g of a pale yellow oil (Note 7). The product is purified by simple distillation to afford 12.84 g (57%) of a clear, colorless oil, bp 83−88°C/50mm (Note 8), (Note 9) and (Note 10).2. Notes1. A Teflon-coated thermocouple of the J-type attached to an Omega model 650 digital thermometer can be substituted for the immersion thermometer.2. Ethyl lactate was purchased from Aldrich Chemical Company, Inc. , and used without further purification. The water content was 0.8 mg/mL by Karl Fisher titration (Metrohm model 684 KF coulometer).3. Tetrahydrofuran was purchased from Fisher Scientific Company and dried over 4 Å molecular sieves for 18 hr prior to use. The water content was less than 0.05 mg/mL by Karl Fisher titration.4. Diphenylphosphoryl azide was 98% as purchased from Aldrich Chemical Company, Inc. , and the water content was less than 0.01 mg/mL by Karl Fisher titration.5. DBU was 98% as purchased from Aldrich Chemical Company, Inc. , and the water content was 0.5 mg/mL by Karl Fisher titration. The amount of DBU was calculated to be 0.93 equiv of the ethyl lactate charge by assuming a purity of 98% for DBU and 100% purity for ethyl lactate . Amounts of base over 1 equiv resulted in product epimerization.6. The reaction typically requires 16-24 hr. The progress of the reaction was monitored by capillary GC after diluting a 0.1-mL sample with 1 mL of methyl tert-butyl ether . GC conditions: Hewlett-Packard 5890 series II GC using an Alltech Econo-cap column (30 M × 0.32 mm × 0.25 μM, catalog # 19646). [The submitters used an HP-5 column (25 M × 0.32 mm × 0.52 mm, HP part # 19091J-112)]. Start oven at 50°C, then increase to 250°C at 10°C per min. The reaction was considered complete after 90% conversion; starting material R t 4.3 min, product R t7.0 min. 7. The vacuum was deliberately bled to maintain 120-130 mm to minimize product losses due to volatility.8. The yield was based on the DBU charge. The product was contaminated with 4-8% of starting material that codistilled with the product. The following characterization data was obtained: ethyl (R)-(+)-2-azidopropionate : [α] D 25 +14.8° ( hexane , c 1.00); 1H NMR (250 MHz, CDCl 3) δ: 1.28 (t, 3 H, J = 7.2), 1.43 (d, 3 H, J = 7.1), 3.89 (q, 1 H, J = 7.1), 4.21 (q, 2 H, J = 7.2) ; 13C NMR (75 MHz, CDCl 3) δ: 14.1, 16.7, 57.3, 61.8, 170.9 ; IR (thin film) cm −1: 2120, 1743 . 9. Optical purity can be quantitatively assayed by HPLC after reducing a sample to the amine with triphenylphosphine . A 50-mg sample was diluted with 10:1 THF:water (1 mL in a screw cap vial) and treated with triphenylphosphine (190 mg). Gas evolution begins within 5 min; once this subsides the reaction is sealed and placed in an oil bath at 50°C for 30 min. The mixture is diluted with HClO 4 (pH 1.0, 1 mL) and washed with dichloromethane (2 × 1 mL). The acidic water phase contains the salt of the amine. A 200-μL sample was diluted to 1 mL and assayed by HPLC using a Crownpak CR(+) column (Diacel Chemical Industries): HPLC conditions; aqueous pH 1.0 HClO 4 , flow 0.5 mL/min, UV detection at 210 nm. The product had an enantiomeric excess of 96%, major enantiomer, R t 3.4 min, and minor enantiomer, R t 5.0 min. 10. The product from the distillation was analyzed by drop weight testing and differential scanning calorimetry (DSC). The drop weight test indicated that the product was not shock sensitive. By DSC, there was a 400 cal/g release of energy which initiated at 135°C. The pot residue showed a slow release of energy which was estimated to be ca. 100 cal/g and initiated at 150°C.Waste Disposal InformationAll toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.3. DiscussionAsymmetric introduction of azide to the α-position of a carbonyl has been achieved by several methods. These include amine to azide conversion by diazo transfer,2 chiral enolate azidation,3 4 and displacement of optically active trifluoromethanesulfonates,5 p-nitrobenzenesulfonates,6 or halides.7 8 Alkyl 2-azidopropionates have been prepared in optically active form by diazo transfer,2 p-nitrobenzenesulfonate displacement,6 and the Mitsunobu displacement using zinc azide .9 The method presented here is the simplest of the displacement methods since alcohol activation and displacement steps occur in the same operation. In cases where the α-hydroxy esters are available, this would be the simplest method to introduce azide.In addition to α-hydroxy carbonyl compounds, the method can be generally applied for alcohol to azide displacements. This method has been successfully demonstrated on fourteen optically active alcohols.10 Mechanistically, this reaction proceeds in two stages. The first is alcohol activation via formation of the corresponding phosphate, and the second stage is the azide displacement step. The method is most useful for azide displacements of alcohols which tend to racemize using highly reactive groups for activation (e.g., sulfonate formation or Mitsunobu conditions 11). When diphenylphosphoryl azide and DBU are used, the alcohol is only mildly activated for displacement as a phosphate. Use of the phosphate thus provides access to azide displacements of alcohols that are too sensitive using standard activation techniques. However, since the phosphate is only mildly activating, the alcohol undergoing displacement should be benzylic, allylic, or as in the present case, α to a carbonyl.Certain classes of compounds are too reactive for the present method. Ethyl mandelate produced a racemic, protected phenyl glycine derivative. Benzylic alcohols with two methoxy groups (directly conjugating in the 2 and 4 positions) gave azide of 50% e.e.Other classes of alcohols are unreactive. Ethyl 3-hydroxybutyrate (a β-hydroxy ester) went to the phosphate stage, but would not undergo azide displacement. In this example about 30% of the crotonate was formed because of β-elimination.References and Notes1.Department of Process Research, Merck Research Laboratories, Rahway, NJ 07065.2.Zaloom, J.; Roberts, D. C. J. Org. Chem.1981, 46, 5173.3.Evans, D. A.; Britton, T. C. J. Am. Chem. Soc.1987, 109, 6881;4.Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am. Chem. Soc.1990, 112, 4011.5.Effenberger, F.; Burkard, U.; Willfahrt, J. Angew. Chem., Int. Ed. Engl.1983, 22, 65. Thetrifluoromethanesulfonate displacements were demonstrated with amines (not azide).6.Hoffman, R. V.; Kim, H. O. Tetrahedron1992, 48, 3007.7.Evans, D. A.; Ellman, J. A.; Dorow, R. L. Tetrahedron Lett.1987, 28, 1123;8.Durst, T.; Koh, K. Tetrahedron Lett.1992, 33, 6799.9.Viaud, M. C.; Rollin, P. Synthesis1990, 130.10.Thompson, A. S.; Humphrey, G. R.; DeMarco, A. M.; Mathre, D. J.; Grabowski, E. J. J. J. Org.Chem.1993, 58, 5886.11.Mitsunobu, O.; Wada, M.; Sano, T. J. Am. Chem. Soc.1972, 94, 679; Lal, B.; Pramanik, B. N.;Manhas, M. S.; Bose, A. K. Tetrahedron Lett.1977, 1977; Fabiano, E.; Golding, B. T.; Sadeghi, M. M. Synthesis1987, 190; Chen, C.-P.; Prasad, K.; Repic, O. Tetrahedron Lett.1991, 32, 7175;Hughes, D. L. Org. React.1992, 42, 335.AppendixChemical Abstracts Nomenclature (Collective Index Number);(Registry Number)Ethyl (R)-2-azidopropionate:Propanoic acid, 2-azido-, ethyl ester, (R)- (12); (124988-44-9)Ethyl (S)-(−)-lactate:Lactic acid, ethyl ester, L- (8);Propanoic acid, 2-hydroxy-, ethyl ester, (S)- (9); (687-47-8)Diphenylphosphoryl azide:Phosphorazidic acid, diphenyl ester (8, 9); (26386-88-9)1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU):Pyrimido[1,2-a]azepine, 2,3,4,6,7,8,9,10-octahydro- (8, 9); (6674-22-2)Methyl tert-butyl ether:Ether, tert-butyl methyl (8);Propane, 2-methoxy-2-methyl- (9); (1634-04-4)Citric acid monohydrate (8);1, 2, 3-Propanetricarboxylic acid, 2-hydroxy-, monohydrate (9); (5949-29-1)Copyright © 1921-2005, Organic Syntheses, Inc. All Rights Reserved。

Organic Syntheses, Coll. Vol. 2, p.580 (1943); Vol. 12, p.76 (1932).THIOSALICYLIC ACID[Benzoic acid, o -mercapto-]Submitted by C. F. H. Allen and D. D. MacKay.Checked by Roger Adams and A. E. Knauf. 1. ProcedureCaution! Recently it was reported to us that workers, following the procedure in Coll. Vol. II, pg 580 (diazotization of anthranilic acid and its reaction with sodium disulfide) but substituting 2,3-dimethylaniline for anthranilic acid, experienced a serious explosion upon addition of the diazonium salt solution to the disulfide solution. We urge that extreme caution should always be exercised in the handling of diazonium salts even when they are in solution.In a 4-l. beaker, 290 cc. of water is heated to boiling, and 260 g. (1.1 moles) of crystallized sodium sulfide (Na 2S·9H 2O) and 34 g. of powdered sulfur are dissolved by heating and stirring. A solution of 40 g. of sodium hydroxide in 100 cc. of water is then added and the mixture cooled, first in cold water, and finally by a freezing mixture of ice and salt.In a 2-l. beaker, set in a freezing mixture and provided with a stirrer and a thermometer for reading temperatures to 0°, are placed 500 cc. of water, 137 g. (1 mole) of anthranilic acid , and 200 cc. of concentrated hydrochloric acid ; the stirrer is started and the mixture cooled to about 6°. Meanwhile 69 g. (1 mole) of sodium nitrite is dissolved in 280 cc. of hot water and the solution cooled in ice; portions are then placed in a separatory funnel of convenient size, supported in such a way that the lower end of the stem extends beneath the surface of the anthranilic acid solution. When the temperature has fallen to 5°, the nitrite solution is run in; about 500 g. of cracked ice is added at such a rate as to keep the temperature below 5°. This takes about ten minutes (Note 1). A drop of the solution should give an immediate blue color with starch-iodide paper.The stirrer and thermometer are now transferred to the alkaline sulfide solution, the temperature of which must be below 5°. The diazo solution is added over a period of twenty to thirty minutes along with 950 g. of ice to prevent the temperature from rising above 5°. When addition is complete, the waterbath is removed and the mixture allowed to warm up to room temperature; after two hours the evolution of nitrogen ceases (Note 2). About 180 cc. of concentrated hydrochloric acid is added until the solution is acid to Congo red paper, and the precipitate of dithiosalicylic acid is filtered and washed with water.To remove the excess sulfur, the precipitate is dissolved by boiling with a solution of 60 g. of anhydrous sodium carbonate (soda ash) in 2 l. of water, and the mixture is filtered while hot. It is divided into five equal parts (Note 3), and the dithiosalicylic acid is reprecipitated as before with concentrated hydrochloric acid. The solid is filtered, the cake being sucked as dry as possible.The moist cake is mixed with 27 g. of zinc dust and 300 cc. of glacial acetic acid in a 1-l. round-bottomed flask, and the mixture is refluxed vigorously for about four hours (Note 4). When the reduction is complete, the mixture is cooled and filtered with suction. The filter cake is washed once with water and then transferred to a 1-l. beaker. The cake is suspended in 200 cc. of water, and the suspension is heated to boiling. The hot solution is made strongly alkaline by the addition of about 40 cc. of 33 per cent aqueous sodium hydroxide solution. The alkaline solution is boiled for about twenty minutes to ensure complete extraction of the product from the filter cake, filtered from the insoluble material (Note 5), and the thiosalicylic acid is then precipitated by the addition of sufficient concentrated hydrochloric acid to make the solution acid to Congo red paper. The product is filtered with suction, washed once with water, and dried in an oven at 100–110°. The yield of a product which melts at 162–163° is 110–130 g. (71–84 per cent of the theoretical amount based on the anthranilic acid).This product is sufficiently pure for most purposes (Note 6).For recrystallization 5 g. of this material is dissolved in 20 cc. of hot 95 per cent alcohol, and 40 cc. of water is added. The solution is boiled with a little decolorizing carbon, filtered hot, and then allowed to cool. The product crystallizes in yellow flakes. The yield of recrystallized material is 4.7 g.; the melting point of the material is 163–164°.2. Notes1. This method is much more rapid than when external cooling alone is used (Org. Syn. Coll. Vol. I, 1941, 374). The total volume of the solution is not important since the insoluble dithiosalicylic acid is readily filtered.2. Foaming sometimes becomes very during the evolution of nitrogen. The addition of a few cubic centimeters of ether from time to time helps to keep this foaming under control.3. The dithiosalicylic acid may be precipitated all at once if desired and the entire amount reduced in one operation. If this is done, the reduction must be carried out in a 5-l. flask fitted with a good stirrer. The mixture needs to be refluxed about ten hours over a ring burner. In the laboratory, this is much less convenient than it is to divide the material and reduce in smaller amounts. The yield is not materially lowered by making the reduction in one portion.4. The reduction does not always run smoothly. If the zinc lumps and becomes inactive more must be added. To determine whether reduction is complete, a sample is removed, cooled, and filtered. The precipitate is boiled with strong sodium hydroxide solution, filtered, and then acidified with hydrochloric acid. If the reduction is complete, the precipitated material will melt at 164° or lower. If the reduction is not complete, the precipitated material will melt above 164°. If the reduction is not complete, the refluxing of the main portion must be continued (and perhaps more zinc must be added) until a test portion shows that the reaction is complete.In determining the melting point of the material, the capillary tube containing the test sample should be inserted in a bath previously heated to 163–164°.5. When the reduction is carried out in five portions, one extraction with sodium hydroxide is usually sufficient for each portion. If the reduction is carried out in one operation, several extractions are usually required. When the material is to be extracted more than once, it is best to boil the residue from the first alkaline treatment with hydrochloric acid, filter, and then treat again with the alkali.6. Thiosalicylic acid is used for the preparation of oxythionaphthene and many thioindigoid dyes.3. DiscussionOf the several methods described for the production of thiosalicylic acid, only the following are of preparative interest: heating o-halogenated benzoic acids with an alkaline hydrosulfide at 150–200° in the presence of copper or copper salts,1, 2 or with sodium sulfide at 200°;3 and reduction of dithiosalicylic acid with glucose,4 or metals5, 2 in alkaline solution. The dithiosalicylic acid is prepared by treating diazotized anthranilic acid with sodium disulfide in alkaline solution.5This preparation is referenced from:z Org. Syn. Coll. Vol. 3, 809References and Notes1.(a) Cassella and Company, Ger. pat. 189,200 [C. A. 2, 607 (1908)]; (b) Cain, "IntermediateProducts for Dyes," p. 151.2.Chem. Age 21, Dyestuffs Suppl. p. 11 (1929).3.Cassella and Company, Ger. pat. 193,290 [C. A. 2, 1514 (1908)]; Ref. 1(b).4.Claasz, Ber. 45, 2427 (1912).5.Kalle and Company, Ger. pat. 204,450 [C. A. 3, 1695 (1909)]; Ref. 1(b).AppendixChemical Abstracts Nomenclature (Collective Index Number);(Registry Number)sodium sulfide (Na2S·9H2O)dithiosalicylic acid sodium carbonate (soda ash) copper or copper saltso-halogenated benzoic acidsalcohol (64-17-5) hydrochloric acid (7647-01-0) acetic acid (64-19-7)ether (60-29-7) sodium hydroxide (1310-73-2) nitrogen (7727-37-9) sodium nitrite(7632-00-0)sulfur (7704-34-9)decolorizing carbon (7782-42-5)zinc (7440-66-6)sodium sulfide (1313-82-2)sodium disulfideAnthranilic Acid (118-92-3)glucose (492-62-6)hydrosulfideThiosalicylic acid,Benzoic acid, o-mercapto- (147-93-3)oxythionaphtheneCopyright © 1921-2005, Organic Syntheses, Inc. All Rights Reserved。

Organic Syntheses, Coll. Vol. 4, p.68 (1963); Vol. 39, p.3 (1959).BENZENEBORONIC ANHYDRIDE[Boroxin, triphenyl-]Submitted by Robert M. Washburn, Ernest Levens, Charles F. Albright, and Franklin A. Billig1.Checked by B. C. McKusick and H. C. Miller.1. ProcedureCaution! Benzeneboronic acid and its anhydride are toxic substances and may irritate mucous tissues such as those of the eyes. In case of contact, carefully wash exposed parts of the body with soap and water (Note 1).The apparatus consists of a four-necked 5-l. round-bottomed Morton flask2 fitted with a 500-ml. graduated dropping funnel with a pressure-equalizing side arm, a 1-l. graduated dropping funnel of the same type, a thermometer, an efficient mechanical stirrer (Note 2), and an inlet for dry nitrogen. The apparatus is thoroughly swept with dry nitrogen, and the reaction flask is charged with 1.5 l. of anhydrous ether, dry nitrogen(Note 3) being used for pressure transfer.Three hundred thirty-six milliliters (312 g., 3 moles) of methyl borate is distilled directly into the 500-ml. dropping funnel shortly before starting the reaction (Note 4). One liter (544 g., 3 moles) of a 3M ethereal solution of phenylmagnesium bromide is pressure-transferred with dry nitrogen to the 1-l. dropping funnel (Note 5). During subsequent operations until the hydrolysis step, a positive pressure of 10–20 mm. of nitrogen is maintained in the closed system by means of a mercury bubbler to prevent access of atmospheric moisture. The ether is cooled to below −60° by a bath of Dry Ice and acetone and is kept below −60° all during the reaction (Note 6). The reactants are added to the well-stirred reaction mixture alternately in small portions, first 10 ml. of methyl borate and then 30 ml. of phenylmagnesium bromide, the rate of addition being as rapid as is possible without the temperature of the mixture rising above −60° (Note 7). Stirring is continued for an additional 20 minutes below −60° after the addition of the reagents is completed.The stirred mixture, maintained at or below 0°, is hydrolyzed by the addition of 200 ml. of distilled water during 5 minutes. It is then neutralized by addition of a solution of 84 ml. of concentrated sulfuric acid in 1.7 l. of distilled water during 15 minutes. The mixture is transferred to a 5-l. separatory funnel, the ether layer is separated, and the aqueous layer is extracted with three 250-ml. portions of ether.The combined ether layer and extracts are transferred to a 5-l. round-bottomed flask equipped with a Hershberg stirrer,3 a dropping funnel, a Claisen head with a water-cooled condenser, an electric heating mantle, and an ice-cooled receiver (Note 8). After approximately one-half of the ether has been removed by distillation from the stirred mixture, 1.5 l. of distilled water is added slowly while the distillation is continued until a head temperature of 100°is reached (Note 9).While stirring is continued, the aqueous distilland is cooled in an ice bath (Note 10). The benzeneboronic acid, which separates as small white crystals, is collected on a Büchner funnel and washed with petroleum ether. The petroleum ether removes traces of dibenzeneborinic acid, which are seen in the hot mother liquor as globules of brown oil and which may color the product. The acid is dehydrated to benzeneboronic anhydride by heating it in an oven at 110° and atmospheric pressure for 6 hours (Note 11). Benzeneboronic anhydride is obtained as a colorless solid, weight 240–247 g. (77–79%) (Note 12), m.p. 214–216°.2. Notes1. A summary of the physiological activity of benzeneboronic acid may be found in reference 4.2. The submitters found that for a preparation of this size a 1-inch Duplex Dispersator (Premier Mill Corp., Geneva, New York) operating at 7500 r.p.m. provided excellent agitation of the heterogeneous reaction mixture. For smaller preparations (1-l. flask) they found that a Stir-O-Vac (Labline, Inc., 217 N. Desplainer St., Chicago 6, Illinois) operating at 5000 r.p.m. was satisfactory. The type of agitation is very important for, whereas the submitters obtained yields of around 91%, the checkers obtained yields of only 77–80% with either a Morton stirrer2 (excessive splashing deposited some of the reaction mixture on the warm upper walls of the flask) or a Polytron dispersion mill type of stirrer (there was too much hold-up in the stirrer housing).3. Tank nitrogen was dried with phosphorus pentoxide.4. Methyl borate (b.p. 68°) forms a 1:1 azeotrope (b.p. 54.6°) with methanol (b.p. 64°).5 Since the presence of even a small amount of methanol reduces the yield considerably more than would be expected from the stoichiometry, 46,7methyl borate stocks should be freshly distilled through a good column to remove as fore-run any methyl borate-methanol azeotrope which may have been formed by hydrolysis during storage.5. Mallinckrodt analytical reagent grade ether, dried over sodium, was used. The methyl borate was the commercial product of American Potash and Chemical Corporation containing 99% ester as received. The phenylmagnesium bromide was purchased as a 3.0M solution in ether from Arapahoe Special Products, Inc., Boulder, Colorado.6. The yield of benzeneboronic anhydride is highly dependent upon the reaction temperature, as the following data of the submitters show. At a reaction temperature of 15° the yield was 49%; at 0°, 76%; −15°, 86%; −30°, 92%; −45°, 92%; −60°, 99%. The yields are based on the combined first and second crops of benzeneboronic acid.7. At a given temperature, the maximum yield of benzeneboronic acid and the minimum amount of by-product dibenzeneborinic acid are obtained when neither reagent is present in excess. The addition of small increments of reactants is a convenient approximation imposed by the difficulty of adjusting stopcocks to small rates of flow. Alternatively, the Hershberg dropping funnel8 or other metering device may be used to maintain the stoichiometry. Addition times, which depend upon the efficiency of stirring and heat transfer, vary from about 1 hour at −60° to 15 minutes at 0°.8. Stirring is helpful during the ether distillation to prevent superheating.9. Small amounts of benzene, phenol, and biphenyl, which may be formed in the reaction, are removed by the steam distillation. Enough water has been added to ensure solution of all of the product.10. The product crystallizes at 43° with a temperature rise to 45°. The solubility of benzeneboronic acid in water (g./100 g. of water) is approximately 1.1 at 0° and 2.5 at 25°; the solubility-temperature relationship is linear to at least 45°.11. If benzeneboronic acid rather than its anhydride is desired, it can be obtained by air-drying the moist acid in a slow stream of air nearly saturated with water. The yield of acid is 282–332 g. One can readily convert the anhydride to the acid by recrystallizing it from water. Benzeneboronic acid gradually dehydrates to the anhydride if left open to the atmosphere at room temperature and 30–40% relative humidity. The melting point observed is that of the anhydride because the acid dehydrates before it melts.12. The submitters report a yield of 91% and state that an additional 27 g. (9%) of acid can be obtained from the aqueous mother liquor.3. DiscussionThe procedure described4,6 is a modification of the method of Khotinsky and Melamed,9who firstreported the preparation of boronic acids from Grignard reagents and borate esters. Benzeneboronic acid and the corresponding anhydride also have been prepared by reaction of phenylmagnesium bromide with boron trifluoride;10 by the reaction of phenyllithium with butyl borate;11 by the reaction of diphenylmercury with boron trichloride;12 by the reaction of benzene with boron trichloride in the presence of aluminum chloride;13 and by the reaction of triphenylborane with boric oxide.14 The present procedure is also applicable to the synthesis of substituted benzeneboronic acids.4 Benzeneboronic acid and its anhydride are of use as starting materials for the synthesis of phenylboron dichloride15 and of various substituted boronic and borinic acids and esters.7,16This preparation is referenced from:z Org. Syn. Coll. Vol. 10, 613References and Notes1.American Potash and Chemical Corporation, Whittier, California.2.Morton, Ind. Eng. Chem., Anal. Ed., 11, 170 (1939); Morton and Redman, Ind. Eng. Chem., 40,1190 (1948).. Syntheses Coll. Vol.2, 117 (1943).4.Washburn, Levens, Albright, Billig, and Cernak, Advances in Chem. Ser., 23, 102 (1959);5.Schlesinger, Brown, Mayfield, and Gilbreath, J. Am. Chem. Soc., 75, 213 (1953).6.Washburn, Billig, Bloom, Albright, and Levens, Advances in Chem. Ser., 32, 208 (1961).7.Seaman and Johnson, J. Am. Chem. Soc., 53, 711 (1931).. Syntheses Coll. Vol.2, 129 (1943).9.Khotinsky and Melamed, Ber., 42, 3090 (1909).10.Krause and Nitsche, Ber., 55B, 1261 (1922); Krause, German pat. 371,467 (1923) [C. A., 18, 992(1924)].11.Brindley, Gerrard, and Lappert, J. Chem. Soc., 1955, 2956.12.Michaelis and Becker, Ber., 15, 180 (1882).13.Muetterties, J. Am. Chem. Soc., 82, 4163 (1960).14.McCusker, Hennion, Ashby, and Rutowski, J. Am. Chem. Soc., 79, 5194 (1957).15.Dandegaonker, Gerrard, and Lappert, J. Chem. Soc., 1957, 2893.ppert, Chem. Revs., 56, 987, 1013 (1956).AppendixChemical Abstracts Nomenclature (Collective Index Number);(Registry Number)petroleum etherboric oxidesulfuric acid (7664-93-9)Benzene (71-43-2)methanol (67-56-1)ether(60-29-7)phenol (108-95-2)nitrogen (7727-37-9)aluminum chloride (3495-54-3)sodium (13966-32-0)Biphenyl (92-52-4)Phenylmagnesium bromide (100-58-3)Diphenylmercury (587-85-9)Phenyllithium (591-51-5)boron trifluoride (7637-07-2)Benzeneboronic anhydrideBoroxin, triphenyl- (3262-89-3)Benzeneboronic acid (98-80-6)methyl boratedibenzeneborinic acidmethyl borate-methanolButyl borate (688-74-4)boron trichloride (10294-34-5)triphenylborane (960-71-4)phenylboron dichloride (873-51-8)phosphorus pentoxide (1314-56-3) Copyright © 1921-2005, Organic Syntheses, Inc. All Rights Reserved。

Organic Syntheses, Vol. 84, p. 306-316 (2007) ; Coll. Vol. 11, p. 1028-1036 (2009).306 CHIRAL LITHIUM AMIDE BASE DESYMMETRIZATION OF ARING FUSED IMIDE: FORMATION OF (3a S ,7a S )-2-[2-(3,4-DIMETHOXYPHENYL)-ETHYL]-1,3-DIOXO-OCTAHYDRO-ISOINDOLE-3a-CARBOXYLIC ACID METHYL ESTER2Glyoxal, MgSOCH 2Cl 2, rtPhMgCl Et 2O, –78 °C to rt2+AcOH reflux 234THF, –78°C MeO 2CCN5NOO H H OMe OMe 3A.B.C.Submitted by Vincent Rodeschini, Nigel S. Simpkins and Fengzhi Zhang.1 Checked by Melissa A. Beenen and Jonathan A. Ellman.1. ProcedureA. 1(S),2(S)-Diph e nyl-N,N'-bis-[1(R)-ph e nyl-e thyl]-e than e-1,2-diamine (2). In a 500-mL, three-necked, round-bottomed fla sk equipped with a N 2 inlet, two septa a nd a ma gnetic stirring ba r is introduced successively CH 2Cl 2 (180 mL) (Note 1) a nd a n a queous glyoxa l solution (9.40 mL, 82.5 mmol, 1.0 equiv) (Note 2) by syringe through one of the septa. One septum is tempora rily removed a nd solid ma gnesium sulfa te (40.0 g) (Note 3) is then added portion-wise over 20 min, while the mixtureis stirred at room temperature. The resulting suspension is stirred for anadditional 10 min, and then (R)-(+)-phenylethylamine (21.0 mL, 20.0 g,165.0 mmol, 2.0 equiv) (Note 4) is introduced dropwise via syringe over a 5min period. The resulting mixture is stirred overnight at room temperature.Magnesium sulfate is removed by filtration and rinsed with CH2Cl2 (2 25mL). The filtrate is then concentrated by rotary evaporation and then furtherdried under high vacuum for 1 h (Note 5) to provide crude bis-imine (1)(Note 6) as an orange oil (21.3 g, 98.0%), which is used directly for the nextstep without further purification. Into a 1-L, three-necked, round-bottomedflask (Note 7) equipped with one low temperature thermometer, one N2 inletand one septum is introduced crude bis-imine 1 (21.3 g) as a solution in Et2O(300 mL) by syringe (Note 8). This solution is cooled to –78 °C (dry ice-acetone bath), and PhMgCl (162 mL, 2.0 M in THF, 325 mmol, 4.0 equiv)(Note 9) is added drop-wise via syringe pump (Note 10) while maintainingthe internal temperature between –78 °C and –75 °C over 2 h (Note 11). Theresulting dark brown mixture is allowed to warm to room temperaturegradually over 4 h, and stirred for an additional 2 h at room temperature. Themixture is then cooled to 4 °C (ice/water bath), and carefully quenched bythe addition of a saturated aqueous NH4Cl solution (200 mL) after removalof the septum over 30 min. The solid that is formed is dissolved by theaddition of de-ionized water (100 mL), and the two phases are separated in a1-L separatory funnel. The aqueous phase is then further extracted with ethylacetate (3 150 mL). The combined organic phases are washed with brine(50.0 mL), then dried over MgSO4 (30 g, 5 min) and filtered. The filtrate isconcentrated by rotary evaporation and further dried under high vacuum for1 h. The crude product (33.5 g) is purified by flash column chromatography.Thus, the crude brown solid is dissolved in the minimum amount of CH2Cl2(approximately 10 mL), charged on a column (8 16 cm) containing 400 gof silica gel (Note 12) and eluted with Et2O-petroleum ether (5:95, 2 L, then10:90, 2 L). After the first apolar impurity (this spot is only evident by UV),the title compound elutes, before a mixture of other isomers (Note 13). Thecombined fractions of the major isomer are concentrated by rotaryevaporation to provide a slightly yellow solid (16.8 g). This solid isdissolved in boiling petroleum ether (250 mL), with addition of a smallamount of CH2Cl2 (5 mL) to complete the dissolution. The solvent is allowedto evaporate to 1/5 of the initial volume at room temperature over 2 days,allowing the crystallisation to occur (Note 14). These crystals are collectedby filtration, and rinsed with a small amount (15.0 mL) of cold (0 °C)307petroleum ether. Thus, 13.8–14.7 g (40–43%) of pure diamine 2 are obtained (Note 15).B. (3aS,7aR)-2-[2-(3,4-Dimethoxyphenyl)-ethyl]-hexahydro-isoindole-1,3-dione (3). Into a 250-mL, one-necked, round-bottomed flask, equipped with a septum and a magnetic stirring bar, containing cyclohexanedicarboxylic anhydride (8.50 g, 55.1 mmol, 1.0 equiv) (Note 16) is added glacial acetic acid (100 mL), followed by 2-(3,4-dimethoxyphenyl)ethylamine (10.1 g, 55.4 mmol, 1.0 equiv) (Note 17). The septum is removed and the flask is equipped with a Liebig condenser. The reaction is then heated at reflux (oil bath temperature 120 °C) for 13 h. The resulting mixture is allowed to cool to room temperature and poured into a 1-L beaker containing 400 mL of de-ionized water. T he aqueous phase is extracted with diethyl ether (5 100 mL). The combined organic phases are transferred into a 1-L Erlenmeyer flask, cooled to 4 °C (water/ice bath) and neutralized by the slow addition (30 min) of a saturated aqueous Na2CO3 solution (150 mL) under vigorous stirring. After the addition is finished, the two phases are separated and the organic phase is further washed with saturated aqueous Na2CO3 (2 50 mL). The organic phase is then dried over anhydrous MgSO4 (20.0 g, 5 min). After removal of the solid by filtration, the organic phase is concentrated by rotary evaporation and further dried under high vacuum for 1 h. The resulting yellow solid is recrystallized from boiling light petroleum ether/ethyl acetate (100 mL:25 mL). Crystallization is allowed to occur at room temperature over 2 h, then at 4 °C overnight. T he crystals are collected by filtration and washed with cold (0 °C) petroleum ether (25 mL) to give 14.2 g (81%) (Note 18) of the title compound 3 (Note 19).C. (3aS,7aS)-2-[2-(3,4-Dimethoxyphenyl)-ethyl]-1,3-dioxo-octahydro-isoindole-3a-carboxylic acid methyl es ter (5). Into a 100-mL, two-necked, round-bottomed flask (Note 7), equipped with one septum and one low temperature thermometer, containing a solution of diamine 2 (8.79 g, 20.9 mmol, 1.1 equiv) in THF (50 mL) (Note 20) cooled to –78 °C (dry ice-acetone bath) is introduced n-BuLi (8.50 mL, 2.5 M in hexanes, 21.3 mmol, 1.1 equiv) (Note 21) dropwise via syringe over 25 min maintaining the internal temperature between –78 °C and –75 °C. The resulting pink solution is allowed to warm to room temperature (23 °C) by removing the cooling bath, and then stirred at this temperature for 30 min (Note 22). This solution is then cooled to –78 °C and transferred over 2 h via cannula into a 250-mL two-necked, round-bottomed flask equipped with one septum and one low 308temperature thermometer containing a solution of imide 3 (6.00 g, 18.9mmol) in THF (80 mL) while maintaining the internal temperature at –78 °C.The resulting mixture is then stirred for 1 h at –78 °C. A solution of methylcyanoformate (3.00 mL, 37.8 mmol, 2.0 equiv) (Note 23) in THF (10 mL) isthen added dropwise via cannula over 15 min. The resulting yellow solutionis stirred for 1 h at –78 °C, then the cooling bath is removed, and saturatedaqueous NaHCO3 (80.0 mL) is added slowly, followed by de-ionized water(20 mL). The phases are separated, and the aqueous phase is extracted withethyl acetate (3 50 mL). The combined organic phases are washed withbrine (50 mL), then dried over MgSO4 (20.0 g, 5 min). After removal of thesolid by filtration, the filtrate is concentrated by rotary evaporation. Thecrude solid residue is dissolved in the minimum amount of CH2Cl2(approximately 15 mL), charged on a column (8 16 cm) containing 400 gof silica gel (Note 12) and eluted with ethyl acetate-petroleum ether (30:70,1 L) to afford recovered diamine2 (8.40 g, 96%) (Note 24), and then withAcOEt-petroleum ether (50:50, 2 L) to afford title compound 5 (6.20 g, 87%) (Note 25).2. Notes1. The checkers used HPLC grade CH2Cl2 purchased from Fisherand passed through two columns of neutral alumina. The submitters usedCH2Cl2 freshly distilled over CaH2 under an Ar atmosphere.2. Glyoxal (40% aqueous solution, ~ 8.8 M) was purchased fromFluka Chemical Company.3. MgSO4 was purchased from Fisher Company and dried in anoven at 120 °C for 24 h.4. (R)-(+)-Phenylethylamine was purchased from LancasterChemical Company {99%, 99% e.e. (HPLC)} and used as received.5. Throughout this procedure, rotary evaporation refers to a vacuumof 20 mmHg, and high vacuum refers to a vacuum of 1 mmHg.6. Crude bis-imine (1) (R f= 0.5; petroleum ether:Et2O 1:1,visualization with KMnO4)7. The apparatus was dried in an oven (120 °C) overnight andmaintained under an atmosphere of dry N2 during the course of the reaction.8. The checkers used ACS grade Et2O stabilized with BHTpurchased from Fisher and passed through two columns of neutral alumina.The submitters used anhydrous Et2O purchased from Fisher Chemicals309(water < 0.03%) and purified by pressure filtration under N2 through activated alumina.9. Phenylmagnesium chloride was obtained from Aldrich Chemical Company, Inc.10. The submitters performed this addition via cannula.11. A white precipitate appeared over the course of the addition.12. The checkers used silica gel 60A (32- 63D) purchased from Bodman Industries. The submitters used silica gel 60A (35-70 ) purchased from Fluorochem.13. The 1H NMR of the crude reaction material indicated a ratio of the title compound (1S, 2S)-2 to the minor isomer (1R, 2R)-2 of 8:2 (R f (major) = 0.4, (minor) = 0.2, petroleum ether:Et2O 4:1, visualization with KMnO4). The minor isomer was identified by a characteristic signal at 3.88 ppm in the 1H NMR,2 and was isolated containing traces of another isomer (3.83 g, brown oil).14. Alternatively, the solution was simply cooled to room temperature, and then left at 4 °C overnight allowing the crystallisation to occur. After collection of a first batch of crystals, the mother liquor was evaporated to 1/5 of its volume to provide a second batch of crystals.15. Large colorless crystals. mp = 113–115 °C; [ ]D25 +190.0 (c = 1.1, CHCl3); FTIR (CHCl3): 3322, 2923, 2859, 1602, 1492, 1454, 1363, 1106, 921, 862 cm-1; 1H NMR (500 MHz, CDCl3) : 1.25 (d, J = 6.6 Hz, 6H), 2.25 (br s, 2 H), 3.37 (s, 2 H), 3.43 (q, J = 6.4 Hz, 2 H), 6.91–7.24 (m,20 H); 13C NMR (125 MHz, CDCl3) : 25.5, 55.1, 65.9, 126.7 (2), 126.8, 128.0, 128.1, 128.5, 141.8, 145.7; HRMS (ES+) m/z calcd for C30H33N2421.2638, found 421.2644; Found: C, 85.46; H, 7.77; N, 6.64. C30H32N2 requires C, 85.67; H, 7.67; N, 6.66%;16. Cyclohexanedicarboxylic anhydride (95%) was purchased from Aldrich Chemical Company, Inc.17. 2-(3,4-Dimethoxyphenyl)ethylamine (98%) was purchased from Alfa Aesar Company.18. The checkers obtained an 82 % yield when the reaction was run on half-scale.19. Small white crystals; R f= 0.4 (petroleum ether: CH2Cl2:AcOEt 2:2:1, visualisation with KMnO4); mp = 86.7–88.1 °C; FTIR (CHCl3) 3004, 2922, 2860, 1693, 1514, 1399, 1233, 1150, 1025, 807 cm-1. 1H NMR (400 MHz, CDCl3) : 1.28 (m, 2 H), 1.37 (m, 2 H), 1.55 (m, 2 H), 1.74 (m, 2 H), 2.72 (m, 2 H), 2.84 (app. t, J = 7.7 Hz, 2 H), 3.70 (app. t, J = 7.4 Hz, 2 H), 3103.81 (s, 3 H), 3.84 (s, 3 H), 6.71–6.76 (m, 3 H); 13C NMR (100 MHz, CDCl3): 21.6, 23.6, 32.9, 39.2, 39.6, 55.8, 55.9, 111.2, 112.0, 121.0, 130.3, 147.7,148.8, 179.7; MS (EI) m/z 317 (M+, 28%), 164 (C10H12O2, 28%), 151(C9H11O2, 28%). HRMS: found 317.1634, calcd for C18H23NO4 317.1627.Found: C, 68.22; H, 7.56; N, 4.40. C18H23NO4 requires C, 68.10; H, 7.31; N,4.42%.20. The checkers used HPLC grade THF purchased from FisherChemicals and passed though two columns of neutral alumina. Thesubmitters used anhydrous THF purchased from Fisher Chemicals (water <0.03%) and purified by pressure filtration under N2 through activatedalumina.21. n-BuLi (2.5 M in hexanes) was purchased from AldrichChemical Company, Inc.22. The initial color of this solution varied from orange to pink, andafter being stirred at room temperature, from pink to purple.23. Methyl cyanoformate (99%) purchased from Aldrich ChemicalCompany, Inc24. The submitters isolated 2 as small white crystals, [ ]D25 +204 (c= 1.05, CHCl3).25. The checkers obtained an 81% yield when the reaction was runon half-scale. [ ]D25 –52.9 (c = 1.1, CHCl3). The submitters obtained anoptical rotation of [ ]D25 –62.0 (c = 1.1, CHCl3). R f= 0.4 (petroleumether:CH2Cl2:AcOEt 2:2:1, visualization with KMnO4); FTIR (CHCl3) 2940,1742, 1701, 1515, 1349, 1234, 1026, 805 cm-1; 1H NMR (400 MHz, CDCl3): 1.10 (m, 1 H), 1.30–1.37 (m, 3 H), 1.48–1.60 (m, 2 H), 1.98 (ddd, J =14.2, 8.5, 4.2 Hz, 1 H), 2.26 (m, 1 H), 2.86 (app. td, J = 7.7, 2.2 Hz, 2 H),3.19 (dd, J = 6.5, 3.7 Hz, 1 H), 3.72 (s, 3 H), 3.73 (m, 2 H), 3.80 (s, 3 H),3.83 (s, 3 H), 6.69–6.75 (m, 3 H);13C NMR (125 MHz, CDCl3) : 20.5, 20.8,21.4, 28.5, 32.7, 39.8, 43.8, 53.3, 54.1, 55.9, 56.0, 111.1, 112.0, 121.1, 129.9,147.8, 148.9, 170.2, 176.1, 177.6; MS (FAB) m/z 375 (M+, 100%), 164(C10H12O2, 90%), 151 (C9H11O2, 35%); HRMS: found 375.1683, calcd forC20H25NO6 375.1682. Found: C, 63.69; H, 6.75; N, 3.65. C20H25NO6 requiresC, 63.99; H, 6.71; N, 3.73. The ee was determined as 86–88% by HPLC(OD column, EtOH:hexanes 10:90, 0.6 mL/min), the retention times were22.5 min (major) and 27 min (minor). The submitters determined the ee was93–95% by HPLC (OD column, EtOH:hexanes 10:90, 0.6 mL/min), theretention times were 35 min (major) and 47 min (minor).311Waste Disposal InformationAll toxic materials were disposed of in accordance with “Destruction of Hazardous Chemicals in the Laboratory”; Lunn, G.; Sansone, E.B. 2nd Ed.; John Wiley & Sons, Inc.3. DiscussionOver the past two decades, the use of chiral lithium amide bases in synthesis has become widespread, enabling the synthesis of chiral building blocks with high selectivity.3 The three main classes of reactions where chiral lithium amide bases have been applied successfully are: (i) deprotonation of prochiral cyclic ketones, (ii) rearrangement of epoxides to allylic alcohols, and (iii) aromatic and benzylic functionalization of tricarbonyl ( 6-arene)chromium complexes. In all these examples, the chiral base selects between enantiotopic protons in kinetically controlled deprotonations of achiral or prochiral substrates. Another fundamentally different process also exists, in which the chiral lithium amide base first acts as a strong base to produce a prochiral carbanion, e.g. an enolate. The stereochemical outcome of the subsequent reaction of the anion with an electrophile is then controlled by the complexed chiral secondary amine. More recently, catalytic variants of some of the reactions described above have emerged. In this case, a substoichiometric amount of the chiral base is used in conjunction with a stoichiometric amount of an achiral base.4 The procedure described herein illustrates the efficient use of a chiral lithium amide base to mediate desymmetrization of a prochiral cyclic imide. Imide 5 has been used successfully in a synthesis of the proposed structure of the alkaloid Jamtine.5 Apart from chiral diamine 2, commercially available bisphenylethylamine in the form of its lithium amide 6 has been used for the desymmetrization of certain imides.6 However, in many cases chiral base 2 has been shown to provide better selectivity. For example, in the case of imide 9 (Table 1, entry 2), the use of lithium amide 6 proved less selective, providing 9 in only 70% ee. It is also noteworthy that 2 can be used as its mono-lithiated form 4, or as its bis-lithiated derivative 7, both species leading to high enantioselectivities. Table 1 gives examples of other types of imides that have been successfully desymmetrized using chiral base 7.312313N Li76Chiral iamine 2 has also been foun to be useful for the desymmetrization of prochiral ketones,7 piperidines,8 various tricarbonyl( 6-arene)chromium complexes,9 asymmetric rearrangement of episulfoxid es,10 asymmetric thia-Sommelet d earomatization,11 an d asymmetric hydrosilylation 12 with good to excellent levels of enantioselectivities.The synthesis of d iamine 2 suffers from a somewhat low yield ; however, it can be easily prepared in large scale.13 Moreover, it can easily be recovered in essentially pure form by column chromatography after the reaction. Two alternative syntheses of 2 have been reported , either using phenyl lithium instead of a Grignard derivative 2 or via pinacol coupling of imines.14 Neither of these method s, however, provid ed better yield s of the product.In summary, the chiral base desymmetrization of imides provides an efficient method to access highly functionalised molecules with high enantioselectivities. This strategy has been applied to the synthesis of natural products,5,15,17 as well as a drug molecule.17Table 1: Examples of Imide Desymmetrization using Base 7.Me 38Entry Electrophile ConditionsProduct Yield ee N Bn91082%92–94%47%94%65%97%115216317TMSCl TMSCl MeI THF, –78 °CTHF, –105 °C LiClTHF, –78 °C1. School of Chemistry, University of Birmingham, Edgbaston,Birmingham, UK, B15 2TT, n.simpkins@.2.Martelli, G.; Morri, S.; Savoia, D. Tetrahedron, 2000, 56, 8367-8374.3.For reviews see (a) Petterson, D.; Amedjkouh, M., Ahlberg, P. In TheChemistry of Organolithium Compounds; Rappoport, Z.; Marek, I. Ed.s;John Wiley and Sons: Chichester, 2006; pp 411–476. (b) O’Brien, P. J.Chem. Soc., Perkin Trans. 1, 1998, 1439-1457; (c) Cox, P.J. ; Simpkins, N.S. Tetrahedron : Asymmetry, 1991, 2, 1-26; (d) Simpkins, N.S., Asymmetric deprotonation reactions using enantiopure lithium amide bases. In Advanced Asymmetric Synthesis; Stephenson, G.R. (Ed.), Blackie Academic, 1996; 111- 125. (e) Koga, K. Pure Appl. Chem.1994, 66, 1487.4.Eames, J. Eur. J. Org. Chem.2002, 393-401 ; see also ref 3.5.Simpkins, N.S.; Gill, C.D. Org. Lett.2003, 5, 535-537.6.Adams, D.J.; Blake, A.J.; Cooke, P.A.; Gill, C.D.; Simpkins, N.S.Tetrahedron 2002, 58, 4603-4615.7.For a recent example see: Armstrong, A.; Ahmed, G.; Dominguez-Fernandez, B.; Hayter, B.R.; Walles, J.S. J. Org. Chem.2002, 67, 8610-8617; see also: Newcombe, N.J.; Simpkins, N.S. J. Chem. Soc., Chem.Commun.1995, 831-833.8.See for example: Yu, M.; Clive, D.L.J.; Yeh, V.S.C.; Kang, S.; Wang, J.Tetrahedron Lett.2004, 45, 2879-2881; Huxford, T.; Simpkins, N.S.Synlett2004, 13, 2295-2298; Goldspink, N.J.; Simpkins, N.S.;Beckman, M. Synlett1999, 8, 1292-1294.9.For a recent contribution in this area: Castaldi, M.P.; Gibson, S.E.;Rudd, M.; White, A.J.P. Angew. Chem. Int. Ed. 2005, 44, 3432-3435. 10. Blake, A.J.; Cooke, P.A.; Kendall, J.D.; Simpkins, N.S.; Westaway, S.J.J. Chem. Soc., Perkin Trans. 1 2000, 153-163.11.McComas, C.C.; Van Vranken, D.L. Tetrahedron Lett.2003, 44, 8203-8205.12.Bette, V.; Mortreux, A.; Ferioli, F.; Martelli, G.; Savoia, D.; Carpentier,J.F. Eur. J. Org. Chem. 2004, 3040-3045.13. Bambridge, K.; Begley, M.J.; Simpkins N.S. Tetrahedron Lett., 1994,35, 3391-339414.Annunziata, R.; Benaglia, M.; Caporale, M.; Raimondi, L. Tetrahedron:Asymmetry, 2002, 13, 2727-2734.15. Blake, A.J.; Gill, C.D.; Greenhalgh, D.A.; Simpkins, N.S.; Zhang, F.Synthesis2005, 19, 3287-329231416. Giblin, G.M.P.; Kirk, D.T.; M itchell, L.; Simpkins, N.S. Org. Lett.2003, 5, 1673-167517. Gill, C.D.; Greenhalgh, D.A.; Simpkins, N.S. Tetrahedron 2003, 59,9213-9230.AppendixChemical Abstracts Nomenclature; (Registry Number)(R)-(+)-Phenylethylamine: Benzenemethanamine, -methyl-, ( R)-; (3886-69-9)Aqueous glyoxal solution: Ethandial; (107-22-2)Phenylmagnesium chloride:Magnesium, chlorophenyl-; (100-59-4)1(S),2(S)-Diphenyl-N,N'-bis-[1(R)-phenyl-ethyl]-ethane-1,2-diamine;(156730-49-3)Cyclohexanedicarboxylic anhydride: 1,3-Isobenzofurandione, hexahydro-;(85-42-7)2-(3,4-Dimethoxyphenyl)ethylamine: Benzeneethanamine, 3,4-dimethoxy-;(120-20-7)(3a S,7a R)-2-[2-(3,4-Dimethoxyphenyl)-ethyl]-hexahydro-isoindole-1,3-dione : 1H-Isoindole-1,3(2H)-dione, 2-[2-(3,4-dimethoxyphenyl)ethyl]-hexahydro-, (3aR,7aS)-rel-; (501085-17-2)Butyllithium; (109-721-8)Methyl cyanoformate: Carbonocyanidic acid, methyl ester (9CI); (17640-15-2)(3a S,7a S)-2-[2-(3,4-Dimethoxyphenyl)-ethyl]-1,3-dioxo-octahydro-isoindole-3a-carboxylic acid methyl ester; (501085-21-8)Nigel Simpkins was born in 1959 in Luton, England. Hecompleted both his undergraduate studies and his Ph.D (with S.V. Ley) at Imperial College, London. He spent one year withK. C. Nicolaou (Philadelphia) before taking his first lectureshipposition at Queen M ary College, University of London. In1988 he moved to the University of Nottingham where he waspromoted to professor in 1995. From 2007 he will be HaworthProfessor of Chemistry at the University of Birmingham. Hisresearch interests include the use of chiral base reagents insynthesis, and the total synthesis of bioactive natural products.315Fengzhi Zhang received his B.S. degree in 2000 and M.S.degree in 2003 from Lanzhou U niversity, China where heworked on marine natural product synthesis with ProfessorYulin Li. He then worked as a medicinal chemist in apharmaceutical company in Shanghai until entering the Ph.D.program with an Overseas Research Scholarship at theU niversity of Nottingham in 2004. U nder the guidance ofProfessor Nigel Simpkins his research focuses on theasymmetric synthesis of erythrinan alkaloids.Vincent Rodeschini graduated from the School of Chemistry ofMulhouse in 2001. In 2004, he received his PhD from theUniversité de Haute Alsace, working under the supervision ofProf. Jacques Eustache on the synthesis of angiogenesisinhibitors. He then moved to the U K as a Marie CuriePostdoctoral Fellow at the university of Nottingham, under thementorship of Prof. Nigel Simpkins (2005-2007). His researchwas focused on the use of bridgehead lithiation to constructbridgehead substituted natural products. In 2007, he joined thepharmaceutical company Novexel, Paris, as a medicinalchemist in the field of antibiotics.Melissa A. Beenen grew up in Oregon and received her BA inchemistry at Northwestern University in 2004. She then beganher doctoral studies at the University of California, Berkeley inthe laboratories of Professor Jonathan A. Ellman. Her graduateresearch has focused on the metal-catalyzed asymmetricsynthesis of amines using N-tert-butanesulfinamde.316。